bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–03–16
seventy papers selected by
Viktor Korolchuk, Newcastle University
  1. The TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis: a novel regulatory mechanism for Lysophagy.
  2. ATG2A acts as a tether to regulate autophagosome-lysosome fusion in neural cells.
  3. Isowalsuranolide targets TrxR1/2 and triggers lysosomal biogenesis and autophagy via the p53-TFEB/TFE3 axis.
  4. Neurofilament accumulation disrupts autophagy in giant axonal neuropathy.
  5. Lysosomal acidification impairment in astrocyte-mediated neuroinflammation.
  6. Glycogen is a neutral cargo of bulk autophagy in Komagataella phaffii.
  7. Mechanisms and functions of lysosomal lipid homeostasis.
  8. Novel 5-HT6R modulators as mTOR-dependent neuronal autophagy inductors.
  9. Direct sensing of dietary ω-6 linoleic acid through FABP5-mTORC1 signaling.
  10. How does autophagy impact neurological function?
  11. Oxidized protein aggregate lipofuscin impairs cardiomyocyte contractility via late-stage autophagy inhibition.
  12. Cellular homeostatic responses to lysosomal damage.
  13. Regulation of autophagy: Insights into O-GlcNAc modification mechanisms.
  14. The deubiquitinase USP45 inhibits autophagy through actin regulation by Coronin 1B.
  15. Menin maintains lysosomal and mitochondrial homeostasis through epigenetic mechanisms in lung cancer.
  16. Oncogenic RAS induces a distinctive form of non-canonical autophagy mediated by the P38-ULK1-PI4KB axis.
  17. Ultrasound-triggered lysosomal alkalinization to block autophagy in tumor therapy.
  18. Fullerenols hijack lysosomes to disrupt inter-organellar crosstalk and block autophagy pre-activated by mTOR inhibitors for cancer cell PANoptosis.
  19. Autophagy Suppresses CCL2 to Preserve Appetite and Prevent Lethal Cachexia.
  20. Lysosome targeted therapies in hematological malignancies.
  21. Multiple regulatory mechanisms, functions and therapeutic potential of chaperone-mediated autophagy.
  22. Unraveling the potential of neuroinflammation and autophagy in schizophrenia.
  23. Presenilins balancing autophagy and extracellular vesicle secretion.
  24. A positive feedback loop between SMAD3 and PINK1 in regulation of mitophagy.
  25. GZ17-6.02 interacts with carboplatin and etoposide to kill neuroblastoma cells.
  26. Quality control of mitochondrial nucleoids.
  27. The mitophagy receptor BNIP3L/Nix coordinates nuclear calcium signaling to modulate the muscle phenotype.
  28. LAMP2-FLOT2 interaction enhances autophagosome-lysosome fusion to protect the septic heart in response to ILC2.
  29. The Women In Autophagy network empowers global equity in science.
  30. The Intersection of Mitophagy and Autism Spectrum Disorder: A Systematic Review.
  31. Nobiletin-mediated autophagy mitigates nanoplastic-induced toxicity in human intestinal Caco-2 cells.
  32. Autophagy in skeletal muscle dysfunction of chronic obstructive pulmonary disease: implications, mechanisms, and perspectives.
  33. A Comprehensive Review of Nanoparticle-Based Drug Delivery for Modulating PI3K/AKT/mTOR-Mediated Autophagy in Cancer.
  34. Chronic mild stress dysregulates autophagy, membrane dynamics, and lysosomal status in frontal cortex and hippocampus of rats.
  35. Polymyxin B induces pigmentation by upregulating ATG2A-ERK/CREB-MITF-PMEL17 signaling axis.
  36. mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS.
  37. Disruption of ER-mitochondria contact sites induces autophagy-dependent loss of P-bodies through the Ca2+-CaMKK2-AMPK pathway.
  38. Ferritinophagy: multifaceted roles and potential therapeutic strategies in liver diseases.
  39. The transcription factor XBP1 regulates mitochondrial remodel and autophagy in spontaneous abortion.
  40. Mechanisms and therapeutic strategies for NLRP3 degradation via post-translational modifications in ubiquitin-proteasome and autophagy lysosomal pathway.
  41. Microglial progranulin differently regulates hypothalamic lysosomal function in lean and obese conditions via cleavage-dependent mechanisms.
  42. ATG9A vesicles are a subtype of intracellular nanovesicle.
  43. Research progress on the mechanisms of acupuncture in improving ischemic stroke through autophagy.
  44. The Dual Role of Chaperone-mediated Autophagy in the Response and Resistance to Cancer Immunotherapy.
  45. Chaperone-mediated autophagy regulates the metastatic state of mesenchymal tumors.
  46. Amphisome plays a role in HBV production and release through the endosomal and autophagic pathways.
  47. Ammonium chloride mitigates the amplification of fish virus by blocking autophagy-dependent replication.
  48. Danuglipron Ameliorates Pressure Overload-Induced Cardiac Remodelling Through the AMPK Pathway.
  49. Liensinine overcomes EGFR-TKI resistance in lung adenocarcinoma through DRP1-mediated autophagy.
  50. Arthropod autophagy molecules facilitate Anaplasma phagocytophilum infection of Ixodes scapularis tick cells.
  51. 5-Methoxytryptophan Attenuates Oxidative Stress-Induced Downregulation of PINK1 and Mitigates Mitochondrial Damage and Apoptosis in Cardiac Myocytes.
  52. Anoctamin5 deficiency enhances ATG9A-dependent autophagy, inducing osteogenesis and gnathodiaphyseal dysplasia-like bone formation.
  53. Ferroptosis and cuproptosis in periodontitis: recent biological insights and therapeutic advances.
  54. The Alternaria alternata Mip1/RAPTOR Mediates Virulence by Regulating Toxin Production and Autophagy.
  55. Loss of the Ubiquitin-Associated Domain of sqstm1/p62 in Zebrafish Causes a Phenotype Resembling Paget's Disease of Bone.
  56. AMPK activation by hepatitis E virus infection inhibits viral replication through attenuation of autophagosomes and promotion of innate immunity.
  57. IGF2BP1-HAX-1 positive feedback loop-mediated HAX-1 overexpression blocks autophagic flux and promotes chemoresistance in nasopharyngeal carcinoma.
  58. Mitigating effects of H3 receptor antagonism on cerebellar autophagic pathways and behavioral phenotypes in BTBR T+ tf/J mouse model of autism spectrum disorder.
  59. Intrinsic differences in mTOR activity mediates lineage-specific responses to cyclophosphamide in mouse and human granulosa cells.
  60. The Aging Substantia Nigra is Characterized by ROS Accumulation Potentially Resulting in Increased Neuroinflammation and Cytoskeletal Remodeling.
  61. Autophagy: regulating the seesaw of bone-fat balance.
  62. Role of Pink1 in Regulating Osteoclast Differentiation during Periodontitis.
  63. Mst1 knockout and Nrf2 activation alleviate diabetic cardiomyopathy pathogenesis through autophagy modulation in type 2 diabetic mice.
  64. Melatonin attenuates inflammatory bone loss by alleviating mitophagy and lactate production.
  65. Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.
  66. SIRT3 mitigates dry eye disease through the activation of autophagy by deacetylation of FOXO1.
  67. Selective regulation of corticostriatal synapses by astrocytic phagocytosis.
  68. Structural basis for anomalous cellular trafficking behavior of glaucoma-associated A427T mutant myocilin.
  69. Structure of human PINK1 at a mitochondrial TOM-VDAC array.
  70. Chinese Medicine for the Treatment of Liver Cirrhosis: The Mechanism of Cellular Autophagy.
  1. Autophagy. 2025 Mar 13.
    The TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis: a novel regulatory mechanism for Lysophagy.
    Na Yeon Park, Dong-Hyung Cho.
      Lysophagy, the selective macroautophagic/autophagic clearance of damaged lysosomes, is a critical mechanism for maintaining cellular homeostasis. Our recent study identified a novel regulatory axis involving TBK1, SCFFBXO3, TMEM192, and TAX1BP1 that orchestrates lysophagic flux following lysosomal damage. We demonstrated that TBK1-dependent phosphorylation of FBXO3 facilitates its interaction with TMEM192, promoting its ubiquitination and subsequent recognition by the autophagy receptor TAX1BP1. Perturbing this pathway significantly reduces lysophagic flux and results in accumulation of damaged lysosomes. These findings establish a previously unrecognized mechanistic link between ubiquitination, receptor recruitment, and lysophagic degradation, broadening our understanding of lysosomal quality control.
    Keywords:  FBXO3; TAX1BP1; TBK1; TMEM192; lysophagy; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2025.2479669
  2. Autophagy. 2025 Mar 13.
    ATG2A acts as a tether to regulate autophagosome-lysosome fusion in neural cells.
    Ze Zheng, Cuicui Ji, Hongyu Zhao, Yan G Zhao.
      The macroautophagy/autophagy proteins ATG2A and ATG2B transfer lipids for phagophore membrane growth. They also form stable complexes with WDR45 and WDR45B. Our previous study demonstrated that WDR45 and WDR45B mediate autophagosome-lysosome fusion in neural cells. Given the defective autophagosome formation in cells lacking both ATG2s, their role in later autophagy stages is hard to explore. Here, we report that in neuroblastoma-derived Neuro-2a (N2a) cells, knocking down (KD) Atg2a, but not Atg2b, results in significant accumulation of SQSTM1/p62 and MAP1LC3/LC3-II, indicating impaired autophagy. Atg2a deficiency does not affect autophagosome formation, but reduces colocalization of autophagosomal LC3 with late endosomal/lysosomal RFP-RAB7, suggesting impaired autophagosome-lysosome fusion. ATG2A interacts with the SNARE proteins STX17, SNAP29, and VAMP8, facilitating their assembly. Overexpression of ATG2A partially rescues the autophagosome-lysosome fusion defects in Wdr45- and Wdr45b-deficient cells. ATG2 and another tether protein, EPG5, function partially redundantly in mediating autophagosome-lysosome fusion. Thus, ATG2A plays a key role in neural autophagy by tethering autophagosomes with lysosomes for fusion.
    Keywords:  ATG2A; WDR45; autophagosome; autophagy; lysosome; tether
    DOI:  https://doi.org/10.1080/15548627.2025.2479427
  3. Sci China Life Sci. 2025 Mar 07.
    Isowalsuranolide targets TrxR1/2 and triggers lysosomal biogenesis and autophagy via the p53-TFEB/TFE3 axis.
    Xu Yang, Xiao Ding, Yueqin Zhao, Yinyuan Wang, Xianxiang Dong, Zhenpeng Niu, Zhijia Gu, Jimin Fei, Yuhan Zhao, Xiaojiang Hao.
      The lysosome is transformed from a major degradative site to a dynamic regulator of cellular homeostasis. Cancer cells with altered redox environments could be exploited as potential targets for cancer therapy. The thioredoxin (Trx) system, which includes thioredoxin reductases (TrxRs), is a promising target for cancer drug development. Here, by identifying the natural product isowalsuranolide (Hdy-7), we showed that lysosomal biogenesis and autophagy are elicited by Hdy-7 via the inhibition of TrxRs. The attenuation of cellular TrxR activity led to the accumulation of ROS, which are indispensable for p53 activation and subsequent lysosomal biogenesis mediated by the transcription factor TFEB/TFE3. Knockdown of TrxR1/2 led to activation of TFEB/TFE3, thereafter increasing lysosomal biogenesis. Treatment with the ROS scavenger NAC or knockdown of p53 or SESN2 led to attenuation of the nuclear translocation of TFEB/TFE3, lysosomal biogenesis, and autophagic flux, suggesting that the TrxR1/2-p53-TFEB/TFE3 axis plays a role in maintaining lysosomal homeostasis under stress conditions other than starvation. Surprisingly, pharmacological inhibition or genetic ablation of autophagy prevented Hdy-7-induced cell death, suggesting that Hdy-7-induced autophagy is detrimental to cancer cells. Our study revealed that Hdy-7 induces ROS-mediated lysosomal biogenesis and retards cell growth by targeting TrxR1/2. This study highlights the lysosome as a regulatory hub for cellular homeostasis and as an attractive therapeutic target for a variety of lysosome-related diseases, including cancer.
    Keywords:  TFEB/TFE3; TrxR1/2; autophagy-lysosomal pathway; lysosomal biogenesis; p53
    DOI:  https://doi.org/10.1007/s11427-023-2563-6
  4. JCI Insight. 2025 Mar 10. pii: e177999. [Epub ahead of print]10(5):
    Neurofilament accumulation disrupts autophagy in giant axonal neuropathy.
    Jean-Michel Paumier, James Zewe, Chiranjit Panja, Melissa R Pergande, Meghana Venkatesan, Eitan Israeli, Shikha Prasad, Natasha Snider, Jeffrey N Savas, Puneet Opal.
      Neurofilament accumulation is associated with many neurodegenerative diseases, but it is the primary pathology in giant axonal neuropathy (GAN). This childhood-onset autosomal recessive disease is caused by loss-of-function mutations in gigaxonin, the E3 adaptor protein that enables neurofilament degradation. Using a combination of genetic and RNA interference approaches, we found that dorsal root ganglia from mice lacking gigaxonin have impaired autophagy and lysosomal degradation through 2 mechanisms. First, neurofilament accumulations interfere with the distribution of autophagic organelles, impairing their maturation and fusion with lysosomes. Second, the accumulations attract the chaperone 14-3-3, which is responsible for the proper localization of the key autophagy regulator transcription factor EB (TFEB). We propose that this dual disruption of autophagy contributes to the pathogenesis of other neurodegenerative diseases involving neurofilament accumulations.
    Keywords:  Autophagy; Cell biology; Neurological disorders; Neuroscience; Ubiquitin-proteosome system
    DOI:  https://doi.org/10.1172/jci.insight.177999
  5. J Neuroinflammation. 2025 Mar 10. 22(1): 72
    Lysosomal acidification impairment in astrocyte-mediated neuroinflammation.
    Jialiu Zeng, Jonathan Indajang, David Pitt, Chih Hung Lo.
      Astrocytes are a major cell type in the central nervous system (CNS) that play a key role in regulating homeostatic functions, responding to injuries, and maintaining the blood-brain barrier. Astrocytes also regulate neuronal functions and survival by modulating myelination and degradation of pathological toxic protein aggregates. Astrocytes have recently been proposed to possess both autophagic activity and active phagocytic capability which largely depend on sufficiently acidified lysosomes for complete degradation of cellular cargos. Defective lysosomal acidification in astrocytes impairs their autophagic and phagocytic functions, resulting in the accumulation of cellular debris, excessive myelin and lipids, and toxic protein aggregates, which ultimately contributes to the propagation of neuroinflammation and neurodegenerative pathology. Restoration of lysosomal acidification in impaired astrocytes represent new neuroprotective strategy and therapeutic direction. In this review, we summarize pathogenic factors, including neuroinflammatory signaling, metabolic stressors, myelin and lipid mediated toxicity, and toxic protein aggregates, that contribute to lysosomal acidification impairment and associated autophagic and phagocytic dysfunction in astrocytes. We discuss the role of lysosomal acidification dysfunction in astrocyte-mediated neuroinflammation primarily in the context of neurodegenerative diseases along with other brain injuries. We then highlight re-acidification of impaired lysosomes as a therapeutic strategy to restore autophagic and phagocytic functions as well as lysosomal degradative capacity in astrocytes. We conclude by providing future perspectives on the role of astrocytes as phagocytes and their crosstalk with other CNS cells to impart neurodegenerative or neuroprotective effects.
    Keywords:  Acidic nanoparticles; Autophagy; Glial crosstalk; Lysosomal acidification; Lysosomal alkalization; Metabolic dysfunction; Neurodegeneration; Neuroinflammation; Neuroprotective; Phagocytosis
    DOI:  https://doi.org/10.1186/s12974-025-03410-w
  6. Autophagy Rep. 2025 ;pii: 2467454. [Epub ahead of print]4(1):
    Glycogen is a neutral cargo of bulk autophagy in Komagataella phaffii.
    Nimna V Wijewantha, Taras Y Nazarko.
      Glycogen is a primary cellular energy store in numerous eukaryotes. Its biosynthesis is a main strategy to cope with forthcoming starvation. During starvation, glycogen is processed in the cytosol or delivered for degradation to animal lysosomes or yeast vacuoles by macroautophagy (hereafter autophagy). However, the mechanism of glycogen autophagy is poorly understood, especially in the heart and skeletal muscles that suffer from the lysosomal glycogen accumulation in Pompe disease. We recently developed the Komagataella phaffii yeast as a simple model to study glycogen autophagy and found that this pathway proceeds non-selectively. However, studies in Saccharomyces cerevisiae proposed glycogen as a non-preferred cargo of bulk autophagy. In our latest study with new fluorescent reporters for glycogen, we clarified cargo properties of K. phaffii glycogen. Both homologous and heterologous markers of glycogen are delivered to the vacuole and degraded with efficiencies that are independent of glycogen, suggesting that glycogen is a neutral cargo of bulk autophagy. This work provides insights into the evolutionary diversity of glycogen autophagy in yeasts with implications for understanding this process in complex eukaryotes.
    Keywords:  CBM20; glycogen granules; glycogen synthase; glycophagy; yeast
    DOI:  https://doi.org/10.1080/27694127.2025.2467454
  7. Cell Chem Biol. 2025 Feb 28. pii: S2451-9456(25)00035-2. [Epub ahead of print]
    Mechanisms and functions of lysosomal lipid homeostasis.
    Michael Ebner, Florian Fröhlich, Volker Haucke.
      Lysosomes are the central degradative organelle of mammalian cells and have emerged as major intersections of cellular metabolite flux. Macromolecules derived from dietary and intracellular sources are delivered to the acidic lysosomal lumen where they are subjected to degradation by acid hydrolases. Lipids derived from lipoproteins, autophagy cargo, or autophagosomal membranes themselves constitute major lysosomal substrates. Dysregulation of lysosomal lipid processing, defective export of lipid catabolites, and lysosomal membrane permeabilization underly diseases ranging from neurodegeneration to metabolic syndromes and lysosomal storage disorders. Mammalian cells are equipped with sophisticated homeostatic control mechanisms that protect the lysosomal limiting membrane from excessive damage, prevent the spillage of luminal hydrolases into the cytoplasm, and preserve the lysosomal membrane composition in the face of constant fusion with heterotypic organelles such as endosomes and autophagosomes. In this review we discuss the molecular mechanisms that govern lysosomal lipid homeostasis and, thereby, lysosome function in health and disease.
    Keywords:  contact sites; lipids; lysosomes; membrane homeostasis; phosphoinositides; signalling
    DOI:  https://doi.org/10.1016/j.chembiol.2025.02.003
  8. Sci Rep. 2025 Mar 11. 15(1): 8380
    Novel 5-HT6R modulators as mTOR-dependent neuronal autophagy inductors.
    José Miguel Alcaíno, Gonzalo Vera, Gonzalo Almarza, Carlos F Lagos, Claudio A Terraza, Andrea Del Campo, Gonzalo Recabarren-Gajardo.
      Autophagy is a natural process in which the cell degrades substances through the lysosomal pathway. One of the most studied mechanisms for regulating autophagy is the mTOR signaling pathway. Recent research has shown that the 5-HT6 receptor is linked to the mTOR pathway and can affect cognition in various neurodevelopmental models. Therefore, developing 5-HT6 receptor antagonists could improve cognition by inducing autophagy through the inhibition of the mTOR pathway. Our study reports two in-house-designed 5-HT6R antagonists, PUC-10 and its indazole analogue PUC-55, that induce mTOR-dependent autophagy. PUC-10, an indole-based 5-HT6 receptor antagonist with high binding affinity (Ki = 14.6 nM) and antagonist potency (IC50 = 32 nM), demonstrated more than 90% at 25 µM cellular viability and a high capacity to induce autophagy in the neuroblastoma SH-SY5Y cell line. Similarly, its indazole analogue, PUC-55 (Ki = 37.5 nM), exhibited high cellular viability and potent autophagy-inducing activity. Both compounds induced overexpression of the 5-HT6 receptor after 24 h of stimulation, contrasting with the effects observed with Rapamycin (100 nM), a well-known mTOR inhibitor. Additionally, the signaling pathway was characterized, showing that both PUC-10 and PUC-55 induce autophagy by inhibiting the mTOR pathway, suggesting their potential therapeutic applications for neurological disorders.
    Keywords:  5-HT6R; Autophagy; Modulators; mTOR
    DOI:  https://doi.org/10.1038/s41598-025-92755-6
  9. Science. 2025 Mar 14. 387(6739): eadm9805
    Direct sensing of dietary ω-6 linoleic acid through FABP5-mTORC1 signaling.
    Nikos Koundouros, Michal J Nagiec, Nayah Bullen, Evan K Noch, Guillermo Burgos-Barragan, Zhongchi Li, Long He, Sungyun Cho, Bobak Parang, Dominique Leone, Eleni Andreopoulou, John Blenis.
      Diet influences macronutrient availability to cells, and although mechanisms of sensing dietary glucose and amino acids are well characterized, less is known about sensing lipids. We defined a nutrient signaling mechanism involving fatty acid-binding protein 5 (FABP5) and mechanistic target of rapamycin complex 1 (mTORC1) that is activated by the essential polyunsaturated fatty acid (PUFA) ω-6 linoleic acid (LA). FABP5 directly bound to the regulatory-associated protein of mTOR (Raptor) to enhance formation of functional mTORC1 and substrate binding, ultimately converging on increased mTOR signaling and proliferation. The amounts of FABP5 protein were increased in tumors and serum from triple-negative compared with those from receptor-positive breast cancer patients, which highlights its potential role as a biomarker that mediates cellular responses to ω-6 LA intake in this disease subtype.
    DOI:  https://doi.org/10.1126/science.adm9805
  10. Neuroscientist. 2025 Mar 13. 10738584251324459
    How does autophagy impact neurological function?
    Angeleen Fleming, Ana Lopez, Matea Rob, Sarayu Ramakrishna, So Jung Park, Xinyi Li, David C Rubinsztein.
      Autophagies describe a set of processes in which cells degrade their cytoplasmic contents via various routes that terminate with the lysosome. In macroautophagy (the focus of this review, henceforth autophagy), cytoplasmic contents, including misfolded proteins, protein complexes, dysfunctional organelles, and various pathogens, are captured within double membranes called autophagosomes, which ultimately fuse with lysosomes, after which their contents are degraded. Autophagy is important in maintaining neuronal and glial function; consequently, disrupted autophagy is associated with various neurologic diseases. This review provides a broad perspective on the roles of autophagy in the CNS, highlighting recent literature that furthers our understanding of the multifaceted role of autophagy in maintaining a healthy nervous system.
    Keywords:  aggregates; autophagy; glia; neural stem cell; neuroinflammation; neuron
    DOI:  https://doi.org/10.1177/10738584251324459
  11. Redox Biol. 2025 Feb 19. pii: S2213-2317(25)00072-2. [Epub ahead of print]81 103559
    Oxidized protein aggregate lipofuscin impairs cardiomyocyte contractility via late-stage autophagy inhibition.
    Sophia Walter, Steffen P Häseli, Patricia Baumgarten, Stefanie Deubel, Tobias Jung, Annika Höhn, Christiane Ott, Tilman Grune.
      Aging of the heart is accompanied by impairment of cardiac structure and function. At molecular level, autophagy plays a crucial role in preserving cardiac health. Autophagy maintains cellular homeostasis by facilitating balanced degradation of cytoplasmic components including organelles and misfolded or aggregated proteins. The age-related decline in autophagy favors an accumulation of protein aggregates such as lipofuscin particularly in the heart, which is composed primarily of non-proliferating cells. Therefore, this study investigates whether lipofuscin accumulation contributes to age-related functional decline of primary adult cardiomyocytes isolated from C57BL/6J mice and examines the role of autophagic flux in mediating these effects. Results showed an age-associated reduction in cardiomyocyte contraction amplitude and an increase in autofluorescence, indicating the accumulation of lipofuscin with age. In vitro treatment of adult primary cardiomyocytes with artificial lipofuscin increased autofluorescence and decreased both contraction amplitude and cellular autophagic flux. Induction of autophagy with rapamycin mitigated contractile dysfunction in lipofuscin-treated cardiomyocytes, whereas inhibition of autophagic flux revealed stage-dependent effects. Late-stage autophagy inhibition using chloroquine or concanamycin A reduced cardiomyocyte contraction amplitude, whereas early-stage autophagy inhibition via 3-methyladenine did not affect contraction within 24 h. In conclusion, our results indicate that lipofuscin directly impairs cardiomyocyte function by diminishing late-stage autophagic flux. These findings highlight the essential role of the autophagy-lysosomal system in preserving age-related loss of cardiomyocyte function caused by accumulating protein aggregates.
    Keywords:  Aging; Contraction; Heart; Lysosome
    DOI:  https://doi.org/10.1016/j.redox.2025.103559
  12. Trends Cell Biol. 2025 Mar 10. pii: S0962-8924(25)00041-8. [Epub ahead of print]
    Cellular homeostatic responses to lysosomal damage.
    Jingyue Jia, Suttinee Poolsup, Jay E Salinas.
      Lysosomes are essential membrane-bound organelles that control cellular homeostasis by integrating intracellular functions with external signals. Their critical roles make lysosomal membranes vulnerable to rupture under various stressors, leading to cellular dysfunction. However, the mechanisms by which cells respond to lysosomal damage have only recently begun to be explored. In this review, we summarize the cellular mechanisms activated by lysosomal damage, emphasizing those that restore lysosomal integrity and sustain homeostasis, including recognition, repair, removal, replacement, and remodeling. Drawing on our expertise, we provide an in-depth focus on the remodeling process involved in these responses, including metabolic signaling and stress granule formation. Finally, we discuss the implications of lysosomal damage in human diseases, underscoring potential therapeutic strategies to preserve lysosomal function and alleviate related disorders.
    Keywords:  damaged lysosomes; recognition; remodeling; removal; repair; replacement
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.007
  13. Life Sci. 2025 Mar 07. pii: S0024-3205(25)00181-X. [Epub ahead of print]369 123547
    Regulation of autophagy: Insights into O-GlcNAc modification mechanisms.
    Chengzhi Liu, Xinyu Wang, Shengnan Xu, Mingyue Liu, Xusheng Cao.
      Autophagy is a "self-eating" biological process that degrades cytoplasmic contents to ensure cellular homeostasis. Its response to stimuli occurs in two stages: Within a few to several hours of exposure to a stress condition, autophagic flow rapidly increases, which is mediated by post-translational modification (PTM). Subsequently, the transcriptional program is activated and mediates the persistent autophagic response. O-linked β-N-acetylglucosamine (O-GlcNAc) modification is an inducible and dynamically cycling PTM; mounting evidence suggests that O-GlcNAc modification participates in the total autophagic process, including autophagy initiation, autophagosome formation, autophagosome-lysosome fusion, and transcriptional process. In this review, we summarize the current knowledge on the emerging role of O-GlcNAc modification in regulating autophagy-associated proteins and explain the different regulatory effects on autophagy exerted by O-GlcNAc modification.
    Keywords:  Autophagy; O-linked β-N-acetylglucosamine modification; Post-translational modification; Regulation; Selective autophagy
    DOI:  https://doi.org/10.1016/j.lfs.2025.123547
  14. J Cell Biol. 2025 May 05. pii: e202407014. [Epub ahead of print]224(5):
    The deubiquitinase USP45 inhibits autophagy through actin regulation by Coronin 1B.
    Yuchieh Jay Lin, Li-Ting Huang, Po-Yuan Ke, Guang-Chao Chen.
      The autophagy-lysosomal system comprises a highly dynamic and interconnected vesicular network that plays a central role in maintaining proteostasis and cellular homeostasis. In this study, we uncovered the deubiquitinating enzyme (DUB), dUsp45/USP45, as a key player in regulating autophagy and lysosomal activity in Drosophila and mammalian cells. Loss of dUsp45/USP45 results in autophagy activation and increased levels of V-ATPase to lysosomes, thus enhancing lysosomal acidification and function. Furthermore, we identified the actin-binding protein Coronin 1B (Coro1B) as a substrate of USP45. USP45 interacts with and deubiquitinates Coro1B, thereby stabilizing Coro1B levels. Notably, the ablation of USP45 or Coro1B promotes the formation of F-actin patches and the translocation of V-ATPase to lysosomes in an N-WASP-dependent manner. Additionally, we observed positive effects of dUsp45 depletion on extending lifespan and ameliorating polyglutamine (polyQ)-induced toxicity in Drosophila. Our findings highlight the important role of dUsp45/USP45 in regulating lysosomal function by modulating actin structures through Coro1B.
    DOI:  https://doi.org/10.1083/jcb.202407014
  15. Cell Death Dis. 2025 Mar 08. 16(1): 163
    Menin maintains lysosomal and mitochondrial homeostasis through epigenetic mechanisms in lung cancer.
    Jun-Bo Yuan, Gui-Xin Gu, Bang-Ming Jin, Qing Han, Bing-Hui Li, Li Zhang, Bin Xu, Xuan Zhu, Guang-Hui Jin.
      Lysosome-mediated autophagy (including mitophagy) is crucial for cell survival and homeostasis. Although the mechanisms of lysosome activation during stress are well recognized, the epigenetic regulation of lysosomal gene expression remains largely unexplored. Menin, encoded by the MEN1 gene, is a chromatin-related protein that is widely involved in gene transcription via histone modifications. Here, we report that menin regulates the transcription of specific lysosomal genes, such as CTSB, CTSE, and TFE3, through MLL-mediated H3K4me3 reprogramming, which is necessary for maintaining lysosomal homeostasis. Menin also directly controls the expression of SQSTM1 and MAP1LC3B to maintain autophagic flux in a manner independent of AMPK/mTORC1 pathways. Furthermore, loss of menin led to mitochondrial dysfunction, elevated levels of reactive oxygen species (ROS), and genome instability. In genetically engineered mouse models, Men1 deficiency resulted in severe lysosomal and mitochondrial dysfunction and an impaired self-clearance ability, which further led to metabolite accumulation. SP2509, a histone demethylase inhibitor, effectively reversed the downregulation of lysosomal and mitochondrial genes caused by loss of Men1. Our study confirms the previously unrecognized biological and mechanistic importance of menin-mediated H3K4me3 in maintaining organelle homeostasis.
    DOI:  https://doi.org/10.1038/s41419-025-07489-0
  16. Cell Res. 2025 Mar 07.
    Oncogenic RAS induces a distinctive form of non-canonical autophagy mediated by the P38-ULK1-PI4KB axis.
    Xiaojuan Wang, Shulin Li, Shiyin Lin, Yaping Han, Tong Zhan, Zhiying Huang, Juanjuan Wang, Ying Li, Haiteng Deng, Min Zhang, Du Feng, Liang Ge.
      Cancer cells with RAS mutations exhibit enhanced autophagy, essential for their proliferation and survival, making it a potential target for therapeutic intervention. However, the regulatory differences between RAS-induced autophagy and physiological autophagy remain poorly understood, complicating the development of cancer-specific anti-autophagy treatments. In this study, we identified a form of non-canonical autophagy induced by oncogenic KRAS expression, termed RAS-induced non-canonical autophagy via ATG8ylation (RINCAA). RINCAA involves distinct autophagic factors compared to those in starvation-induced autophagy and incorporates non-autophagic components, resulting in the formation of non-canonical autophagosomes with multivesicular/multilaminar structures labeled by ATG8 family proteins (e.g., LC3 and GABARAP). We have designated these structures as RAS-induced multivesicular/multilaminar bodies of ATG8ylation (RIMMBA). A notable feature of RINCAA is the substitution of the class III PI3K in canonical autophagy with PI4KB in RINCAA. We identified a regulatory P38-ULK1-PI4KB-WIPI2 signaling cascade governing this process, where ULK1 triggers PI4KB phosphorylation at S256 and T263, initiating PI4P production, ATG8ylation, and non-canonical autophagy. Importantly, elevated PI4KB phosphorylation at S256 and T263 was observed in RAS-mutated cancer cells and colorectal cancer specimens. Inhibition of PI4KB S256 and T263 phosphorylation led to a reduction in RINCAA activity and tumor growth in both xenograft and KPC models of pancreatic cancer, suggesting that targeting ULK1-mediated PI4KB phosphorylation could represent a promising therapeutic strategy for RAS-mutated cancers.
    DOI:  https://doi.org/10.1038/s41422-025-01085-9
  17. Biomaterials. 2025 Mar 08. pii: S0142-9612(25)00169-3. [Epub ahead of print]320 123250
    Ultrasound-triggered lysosomal alkalinization to block autophagy in tumor therapy.
    Yong Liu, Bowen Li, Run Yang, Chenxu Shang, Yang Bai, Bin Zheng, Liang Zhao.
      Lysosomes play a crucial role in regulating cancer progression and drug resistance. However, there is a pressing need for the development of drugs that can safely and effectively modulate the pH of cancerous lysosomes in a controlled manner. In this study, we propose a novel strategy for lysosomal alkalinization triggered by piezoelectricity. Our findings indicate that the electrons generated by (BaTiO3/Zr/Ca) BCZT under sonication effectively alkalinize the lysosomes. Molecular dynamics simulations further demonstrate that alterations in lysosomal pH lead to modifications in the conformation of V-ATPase (proton pump), enhancing its interaction with sodium ions while partially excluding hydrogen ions from entering the lysosomes. This mechanism helps maintain lysosomal alkalization, resulting in reduced hydrolase activity and preventing the degradation of proteins and damaged organelles. The accumulation of nanoparticles within the lysosomes causes swelling and gradual destruction of the lysosomal membrane. Consequently, this lysosomal dysfunction hampers the fusion with autophagosomes, inhibiting autophagy in tumor cells and promoting apoptosis in various tumor types. Our strategy significantly inhibited tumor volume growth in mice during animal studies. In conclusion, our piezoelectric-triggered lysosomal alkalinization strategy holds promise for innovative breakthroughs in the treatment of multiple cancers.
    Keywords:  Autophagy; Lysosome alkalization; Piezoelectric nanomaterials; Tumor therapy
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123250
  18. Sci Bull (Beijing). 2025 Feb 25. pii: S2095-9273(25)00200-2. [Epub ahead of print]
    Fullerenols hijack lysosomes to disrupt inter-organellar crosstalk and block autophagy pre-activated by mTOR inhibitors for cancer cell PANoptosis.
    Hedong Qi, Xue Li, Jing Ma, Jiacheng Sun, Yating Liu, Xin Wang, Kelong Fan, Chunying Shu, Chunru Wang.
      Subcellular inter-organellar crosstalk among lysosome, endoplasmic reticulum (ER), and mitochondrion is crucial for cancer cell survival and is a promising target in cancer treatment; however, efficiently disrupting these interactive networks is challenging. Herein, a communication interception strategy is presented, which specifically disrupts inter-organellar crosstalk by lysosomal contents leakage along with their trajectory and pre-activates autophagic flux to augment the lysosome-associated autophagy blocking for preventing the self-repair of this subcellular disorder. Briefly, fullerenols containing multiple hydroxyl groups (MF) tear the lysosomal phospholipid membrane through direct interaction, which causes lysosomal contents (calcium ions and cathepsins) to leak into the cytoplasm, subsequently leading to endoplasmic reticulum stress and mitochondrial dysfunction with redox imbalance and metabolic reprogramming. mTOR inhibitors activate and amplify autophagy, then impaired lysosomes prevent their fusion with autophagosome, and thus autophagy is paralyzed along with autolysosome accumulation. Consequently, the cellular homeostasis is compromised by destroyed inter-organellar networks without self-repair by autophagy, thereby triggering PANoptotic processes and leading to a remarkable anti-tumor therapeutic efficacy in vitro and in vivo. This strategy demonstrates the selective cytotoxicity of non-toxic nanomaterials that interfere with subcellular inter-organellar crosstalk, offering a novel method for designing tumor therapies.
    Keywords:  Autophagy; Biomaterials; Calcium overload; Inter-organellar crosstalk; PANoptosis
    DOI:  https://doi.org/10.1016/j.scib.2025.02.034
  19. bioRxiv. 2025 Feb 24. pii: 2025.02.20.638910. [Epub ahead of print]
    Autophagy Suppresses CCL2 to Preserve Appetite and Prevent Lethal Cachexia.
    Maria Ibrahim, Maria Gomez-Jenkins, Adina Scheinfeld, Zhengqiao Zhao, Eduardo Cararo Lopes, Akshada Sawant, Zhixian Hu, Aditya Dharani, Michael Sun, Sarah Siddiqui, Emily T Mirek, Johan Abram-Saliba, Edmund C Lattime, Xiaoyang Su, Tobias Janowitz, Marcus D Goncalves, Steven M Dunn, Yuri Pritykin, Tracy G Anthony, Joshua D Rabinowitz, Eileen White.
      Macroautophagy (autophagy hereafter) captures intracellular components and delivers them to lysosomes for degradation and recycling 1 . In adult mice, autophagy sustains metabolism to prevent wasting by cachexia and to survive fasting, and also suppresses inflammation, liver steatosis, neurodegeneration, and lethality 2,3 . Defects in autophagy contribute to metabolic, inflammatory and degenerative diseases, however, the specific mechanisms involved were unclear 4 . Here we profiled metabolism and inflammation in adult mice with conditional, whole-body deficiency in an essential autophagy gene and found that autophagy deficiency altered fuel usage, and reduced ambulatory activity, energy expenditure, and food intake, and elevated circulating GDF15, CXCL10, and CCL2. While deletion of Gdf15 or Cxcl10 provided no or mild benefit, deletion of Ccl2 restored food intake, suppressed cachexia and rescued lethality of autophagy-deficient mice. To test if appetite suppression by CCL2 was responsible for lethal cachexia we performed single nucleus RNA sequencing of the hypothalamus, the center of appetite control in the brain. Notably, we found that autophagy deficiency was specifically toxic to PMCH and HCRT neurons that produce orexigenic neuropeptides that promote food intake, which was rescued by deficiency in CCL2. Finally, the restoration of food intake via leptin deficiency prevented lethal cachexia in autophagy-deficient mice. Our findings demonstrate a novel mechanism where autophagy prevents induction of a cachexia factor, CCL2, which damages neurons that maintain appetite, the destruction of which may be central to degenerative wasting conditions.
    Key points of paper: 1) Autophagy-deficient mice have reduced food intake, systemic inflammation, and cachexia2) CCL2, but not GDF15 or CXCL10, induces lethal cachexia caused by autophagy defect3) Autophagy-deficient mice have CCL2-dependent destruction of appetite-promoting neurons in the hypothalamus4) Leptin deficiency restores appetite and rescues lethal cachexia in autophagy-deficient mice5) Autophagy-deficient mice die from cachexia mediated by appetite loss6) Degenerative conditions due to impaired autophagy are caused by the inflammatory response to the damage7) Targeting CCL2 may be a viable approach to prevent degenerative wasting disorders.
    DOI:  https://doi.org/10.1101/2025.02.20.638910
  20. Front Oncol. 2025 ;15 1549792
    Lysosome targeted therapies in hematological malignancies.
    Madhumita S Manivannan, Anthea Peters, Spencer B Gibson.
      Lysosomes are dynamic organelles integral to cellular homeostasis, secretory pathways, immune responses, and cell death regulation. In cancers, lysosomes become dysregulated to sustain proliferative signaling, metabolism, and invasion. In hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL), leukemia cells demonstrate lysosome dysregulation with increased lysosomal activity, mTORC1 signaling, catabolic reactions, and autophagy. This supports the survival, metabolism, and proliferation of the leukemia cells. Lysosomes also play a critical role in treatment resistance by promoting cell survival and sequestration of drugs. This has led to the development of lysosome-targeted therapies such as cationic amphiphilic drugs (CAD), ATPase inhibitors or autophagy inhibitors to treat hematological malignancies. Lysosome-targeted treatments have shown effectiveness at inducing cell death by inhibiting cell survival mechanisms and inducing apoptosis. In addition, the combination of lysosome-targeted therapies with standard treatments gives synergistic apoptotic responses in leukemia cells. In this review, we will describe the lysosomal functions, their dysregulation in hematological malignancies and the development of lysosomal targeted therapies for leukemia treatment. By understanding lysosome dysregulation and developing lysosome-targeted agents, innovative treatment strategies could be effective in overcoming drug resistance in hematological malignancies.
    Keywords:  autophagy; chemotherapy resistance; drug resistance; hematological malignancies; leukemia; lysosomal dysfunction; lysosomes; targeted treatment
    DOI:  https://doi.org/10.3389/fonc.2025.1549792
  21. Theranostics. 2025 ;15(7): 2778-2793
    Multiple regulatory mechanisms, functions and therapeutic potential of chaperone-mediated autophagy.
    Yuhan Wang, Jingwei Liu, Hao Wang, Pengcheng Jiang, Liangzi Cao, Songming Lu, Siyi Zhang, Ruohan Yang, Hao Feng, Liu Cao, Xiaoyu Song.
      Autophagy refers to the proteolytic degradation of cytoplasmic components by lysosomes, and includes three defined types: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. Although the regulatory pathways of macroautophagy are well defined, how CMA is accurately regulated remains less understood. In recent years, emerging evidence has suggested that chaperone-mediated autophagy is regulated by multiple mechanisms at nucleic acid and protein levels. In this review, we summarized recent progress on multiple regulatory mechanisms and functions concerning CMA, as well as novel treatments targeting specific regulation sites.
    Keywords:  Hsc70; LAMP2A.; autophagy; chaperone-mediated autophagy; post-translational modifications
    DOI:  https://doi.org/10.7150/thno.107761
  22. Eur J Pharmacol. 2025 Mar 05. pii: S0014-2999(25)00223-7. [Epub ahead of print]997 177469
    Unraveling the potential of neuroinflammation and autophagy in schizophrenia.
    Hongxia Tao, Congyin Wang, Chuan Zou, Hongru Zhu, Wei Zhang.
      Schizophrenia (SCZ) is a complex and chronic psychiatric disorder that affects a significant proportion of the global population. Although the precise etiology of SCZ remains uncertain, recent studies have underscored the involvement of neuroinflammation and autophagy in its pathogenesis. Neuroinflammation, characterized by hyperactivated microglia and markedly elevated pro-inflammatory cytokines, has been observed in postmortem brain tissues of SCZ patients and is closely associated with disease severity. Autophagy, a cellular process responsible for eliminating damaged components and maintaining cellular homeostasis, is believed to play a pivotal role in neuronal health and the onset of SCZ. This review explores the roles and underlying mechanisms of neuroinflammation and autophagy in SCZ, with a particular focus on their intricate interplay. Additionally, we provide an overview of potential therapeutic strategies aimed at modulating neuroinflammation and autophagy, including nutritional interventions, anti-inflammatory drugs, antipsychotics, and plant-derived natural compounds. The review also addresses the dual effects of antipsychotics on autophagy. Our objective is to translate these insights into clinical practice, expanding the therapeutic options available to improve the overall health and well-being of individuals with SCZ.
    Keywords:  Autophagy; Neuroinflammation; Schizophrenia; Therapeutic strategy
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177469
  23. Nat Struct Mol Biol. 2025 Mar 11.
    Presenilins balancing autophagy and extracellular vesicle secretion.
    Melina Casadio.
      
    DOI:  https://doi.org/10.1038/s41594-025-01513-9
  24. Cell Discov. 2025 Mar 11. 11(1): 22
    A positive feedback loop between SMAD3 and PINK1 in regulation of mitophagy.
    Mingzhu Tang, Dade Rong, Xiangzheng Gao, Guang Lu, Haimei Tang, Peng Wang, Ning-Yi Shao, Dajing Xia, Xin-Hua Feng, Wei-Feng He, Weilin Chen, Jia-Hong Lu, Wei Liu, Han-Ming Shen.
      PTEN-induced kinase-1 (PINK1) is a crucial player in selective clearance of damaged mitochondria via the autophagy-lysosome pathway, a process termed mitophagy. Previous studies on PINK1 mainly focused on its post-translational modifications, while the transcriptional regulation of PINK1 is much less understood. Herein, we reported a novel mechanism in control of PINK1 transcription by SMAD Family Member 3 (SMAD3), an essential component of the transforming growth factor beta (TGFβ)-SMAD signaling pathway. First, we observed that mitochondrial depolarization promotes PINK1 transcription, and SMAD3 is likely to be the nuclear transcription factor mediating PINK1 transcription. Intriguingly, SMAD3 positively transactivates PINK1 transcription independent of the canonical TGFβ signaling components, such as TGFβ-R1, SMAD2 or SMAD4. Second, we found that mitochondrial depolarization activates SMAD3 via PINK1-mediated phosphorylation of SMAD3 at serine 423/425. Therefore, PINK1 and SMAD3 constitute a positive feedforward loop in control of mitophagy. Finally, activation of PINK1 transcription by SMAD3 provides an important pro-survival signal, as depletion of SMAD3 sensitizes cells to cell death caused by mitochondrial stress. In summary, our findings identify a non-canonical function of SMAD3 as a nuclear transcriptional factor in regulation of PINK1 transcription and mitophagy and a positive feedback loop via PINK1-mediated SMAD3 phosphorylation and activation. Understanding this novel regulatory mechanism provides a deeper insight into the pathological function of PINK1 in the pathogenesis of neurodegenerative diseases such as Parkinson's disease.
    DOI:  https://doi.org/10.1038/s41421-025-00774-4
  25. Anticancer Drugs. 2025 Mar 12.
    GZ17-6.02 interacts with carboplatin and etoposide to kill neuroblastoma cells.
    Michael R Booth, Laurence Booth, Jane L Roberts, Cameron West, Paul Dent.
      The biology of GZ17-6.02 alone and more so in combination with either of the standard-of-care agents etoposide or carboplatin killed MYCN overexpressing neuroblastoma (NB) cells is unknown. The methods involved in this study are in-cell immunoblotting, trypan blue exclusion, plasmid and siRNA transfection, assessment of autophagy using a plasmid expressing LC3-GFP-RFP. GZ17-6.02 (602) comprises, by mass, a ratio of curcumin (1.0), harmine (1.3), and isovanillin (7.7). In tumors dosed with 602, the ratio becomes curcumin (1.0), harmine (16), and isovanillin (6.1) (602NR). GZ17-6.02 activated ATM, AMPK, ULK1, ATG13, and PERK and inactivated ERBB1, ERBB2, ERBB3, ERBB4, AKT, mTORC1, mTORC2, SRC, NFκB, YAP, and eIF2α. 602 enhanced autophagosome formation and autophagic flux that was amplified when it was combined with etoposide or carboplatin. Compared with 602, 602NR caused significantly greater autophagosome formation that was also amplified when in combination with chemotherapy and which was reduced ~40% by knockdown of ATM or AMPKα and abolished by knockdown of Beclin1 or ATG5. Knockdown of ATM or AMPKα significantly reduced tumor cell death caused by 602 of 602NR, whereas endoplasmic reticulum stress (eIF2α) and macroautophagy (Beclin1, ATG5) were more effective at maintaining tumor cell survival. Combined knockdown of Beclin1 and the death receptor CD95 almost abolished the antitumor actions of 602 and 602NR. 602, and more so 602NR, kills MYCN NB cells and interacts with standard-of-care chemotherapeutics to cause further killing via autophagy and death receptor signaling.
    DOI:  https://doi.org/10.1097/CAD.0000000000001708
  26. Trends Cell Biol. 2025 Mar 07. pii: S0962-8924(25)00039-X. [Epub ahead of print]
    Quality control of mitochondrial nucleoids.
    Hao Liu, Haixia Zhuang, Du Feng.
      Mitochondrial nucleoids, organized complexes that house and protect mitochondrial DNA (mtDNA), are normally confined within the mitochondrial double-membrane system. Under cellular stress conditions, particularly oxidative and inflammatory stress, these nucleoids can undergo structural alterations that lead to their aberrant release into the cytoplasm. This mislocalization of nucleoid components, especially mtDNA, can trigger inflammatory responses and cell death pathways, highlighting the critical importance of nucleoid quality control mechanisms. The release of mitochondrial nucleoids occurs through specific membrane channels and transport pathways, fundamentally disrupting cellular homeostasis. Cells have evolved multiple clearance mechanisms to manage cytoplasmic nucleoids, including nuclease-mediated degradation, lysosomal elimination, and cellular excretion. This review examines the molecular mechanisms governing nucleoid quality control and explores the delicate balance between mitochondrial biology and cellular immunity. Our analysis provides insights that could inform therapeutic strategies for mtDNA-associated diseases and inflammatory disorders.
    Keywords:  mitochondria; mitophagy; mtDNA; nucleoid-phagy; nucleoids
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.005
  27. Autophagy. 2025 Mar 10.
    The mitophagy receptor BNIP3L/Nix coordinates nuclear calcium signaling to modulate the muscle phenotype.
    Jared T Field, Donald Chapman, Yan Hai, Saeid Ghavami, Adrian R West, Berkay Ozerklig, Ayesha Saleem, Julia Kline, Asher A Mendelson, Jason Kindrachuk, Barbara Triggs-Raine, Joseph W Gordon.
      Mitochondrial quality control is critical in muscle to ensure contractile and metabolic function. BNIP3L/Nix is a BCL2 member, a mitophagy receptor, and has been implicated in muscle atrophy. Human genome-wide association studies (GWAS) suggest altered BNIP3L expression could predispose to mitochondrial disease. To investigate BNIP3L function, we generated a muscle-specific knockout model. bnip3l knockout mice displayed a ragged-red fiber phenotype, along with accumulation of mitochondria and endo/sarcoplasmic reticulum with altered morphology. Intriguingly, bnip3l knockout mice were more insulin sensitive with a corresponding increase in glycogen-rich muscle fibers. Kinome and gene expression analyses revealed that bnip3l knockout impairs NFAT and MSTN (myostatin) signaling, with alterations in muscle fiber-type and evidence of regeneration. Mechanistic experiments demonstrated that BNIP3L modulates mitophagy, along with reticulophagy leading to altered nuclear calcium signaling. Collectively, these observations identify novel roles for BNIP3L coordinating selective autophagy, oxidative gene expression, and signaling pathways that maintain the muscle phenotype.
    Keywords:  BNIP3L/Nix; calcium signaling; mitophagy; muscle; myostatin
    DOI:  https://doi.org/10.1080/15548627.2025.2476872
  28. Autophagy. 2025 Mar 11. 1-23
    LAMP2-FLOT2 interaction enhances autophagosome-lysosome fusion to protect the septic heart in response to ILC2.
    Rongjiao Shao, Weizhuo Liu, Yuxiao Feng, Xiaoyu Guo, Zhenyu Ren, Xumin Hou, Bin He.
      Cardiac dysfunction is a serious complication of sepsis-induced multiorgan failure in intensive care units and is characterized by an uncontrolled immune response to overwhelming infection. Type 2 innate lymphoid cells (ILC2s), as a part of the innate immune system, play a crucial role in the inflammatory process of heterogeneous cardiac disorders. However, the role of ILC2 in regulating sepsis-induced cardiac dysfunction and its underlying mechanism remain unknown. The present study demonstrated that autophagic flux blockage exacerbated inflammatory response and cardiac dysfunction, which was associated with mortality of sepsis. Using a cecal ligation and puncture (CLP) mouse sepsis model, we observed an expansion of ILC2s in the septic heart. Furthermore, IL4 derived from ILC2 mitigated cardiac inflammatory responses and improved cardiac function during sepsis. Additionally, IL4 enhanced LAMP2 (lysosomal associated membrane protein 2) expression through STAT3 (signal transducer and activator of transcription 3) activation to stabilize lysosomal homeostasis and rescue the impaired autophagic flux during sepsis. Notably, LAMP2 was preferentially bound to FLOT2 (flotillin 2) after IL4 exposure, and the interaction enhanced autophagosome-lysosome fusion in cardiac endothelial cells. Loss of FLOT2 reversed the regulatory effects of LAMP2 on autophagy mediated by IL4, leading to autophagosome accumulation and suppressed autophagosome clearance. Conclusively, these findings provide novel insights that ILC2 regulates incomplete autophagic flux to protect septic heart and expand our understanding of immunoregulation for sepsis.Abbreviation: ACTB: actin beta; ACTN: actinin, alpha; ADGRE1/F4/80: adhesion G protein-coupled receptor E1; ANXA5/annexin V: annexin A5; AO: acridine orange; BECN1/Beclin1: beclin 1, autophagy related; CKM: creatine kinase, muscle; CKB: creatine kinase, brain; CLP: cecal ligation and puncture; CO: cardiac output; CQ: chloroquine; CTS: cathepsin; DAPI: 4'6-diamidino-2-phenylindole; EC: endothelial cell; EF: ejection fraction; ELISA: enzyme-linked immunosorbent assay; FLOT: flotillin; FS: fractional shortening; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GATA3: GATA binding protein 3; GLB1/β-Gal: galactosidase, beta 1; HCMEC: human cardiac microvascular endothelial cell; IL: interleukin; ILC: innate lymphoid cell; IL1RL1/ST2: interleukin 1 receptor-like 1; IL4c: IL4 complex; IL7R/CD127: interleukin 7 receptor; KEGG: Kyoto Encyclopedia of Genes and Genomes; LAMP: lysosomal-associated membrane protein; LDH: lactate dehydrogenase; LMP: lysosome membrane permeabilization; LPS: lipopolysaccharide; LVEDd: left ventricular end-diastole diameter; LVEDV: left ventricular end-diastole volume; LVESd: left ventricular end-systolic diameter; LVESV: left ventricular end-systole volume; MAN: mannosidase alpha; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MS: mass spectrometry; PECAM1/CD31: platelet/endothelial cell adhesion molecule 1; PTPRC/CD45: protein tyrosine phosphatase receptor type C; RORC/RORγt: RAR related orphan receptor gamma; SQSTM1/p62: sequestosome 1; TBX21/T-bet: T-box 21; TEM: transmission electron microscopy; THY1/CD90.2: thymus cell antigen 1, theta; TNF/TNF-α: tumor necrosis factor; V-ATPase: vacuolar-type H+-translocating ATPase; VIM: vimentin.
    Keywords:  Autophagic flux blockage; IL4; STAT3; cardiac dysfunction; lysosome; sepsis
    DOI:  https://doi.org/10.1080/15548627.2025.2469207
  29. Nat Aging. 2025 Mar 12.
    The Women In Autophagy network empowers global equity in science.
    Women in Autophagy
      
    DOI:  https://doi.org/10.1038/s43587-025-00839-9
  30. Int J Mol Sci. 2025 Feb 28. pii: 2217. [Epub ahead of print]26(5):
    The Intersection of Mitophagy and Autism Spectrum Disorder: A Systematic Review.
    Eleonora Kovacheva, Maria Gevezova, Nikolay Mehterov, Maria Kazakova, Victoria Sarafian.
      Autism spectrum disorder (ASD) is a group of neurodevelopmental and biobehavioral conditions that arises from complex interactions between environmental factors and physiological development in genetically predisposed individuals. Among the most frequently observed metabolic abnormalities in ASD is mitochondrial dysfunction. Mitochondria respond to cellular stress by altering their dynamics or initiating mitophagy. In neurons, the buildup of dysfunctional mitochondria and reactive oxygen species (ROS) poses a significant risk, as these cells cannot regenerate through division. To safeguard mitochondrial health, cells rely on an efficient "clean-up mechanism" to remove compromised organelles. Mitophagy, a specific form of autophagy, is responsible for regulating the turnover of flawed and non-functional mitochondria. Impairments in this process result in the accumulation of defective mitochondria in neurons, a characteristic of several neurodegenerative disorders associated with behavioral abnormalities. This systematic review offers an in-depth summary of the present knowledge of mitophagy and underscores its pivotal role in the pathogenesis of ASD.
    Keywords:  autism; mitophagy; pathways
    DOI:  https://doi.org/10.3390/ijms26052217
  31. FASEB J. 2025 Mar 31. 39(6): e70452
    Nobiletin-mediated autophagy mitigates nanoplastic-induced toxicity in human intestinal Caco-2 cells.
    Junho Yu, Ji-Hwan Yoon, Miey Park, Hae-Jeung Lee.
      The presence of nanoplastics (NPs), which cause oxidative stress and damage to the cell structure due to the breakdown of microplastics (MPs), poses considerable ecological and health challenges. This study investigated the protective role of nobiletin (NOB), a flavonoid derived from citrus peel, in modulating autophagy and mitigating NP-induced toxicity in human intestinal Caco-2 cells. The Caco-2 cells were treated with NPs and varying concentrations of NOB to evaluate cell viability, apoptosis, and autophagic activity. We observed that exposure to NPs resulted in a concentration-dependent decrease in cell viability and an increase in the expression of apoptosis markers. Exposure to NPs reduced Caco-2 cell viability and disrupted autophagic processes by decreasing LC3B and increasing p62 levels, indicating impaired autophagy. NOB treatment reversed these effects by enhancing autophagic activity by upregulating LC3B and downregulating p62. Furthermore, NOB improved lysosomal integrity and decreased apoptotic markers such as Bax and cleaved caspase-3 while increasing Bcl-2 expression. NOB also facilitated the nuclear translocation of transcription factor EB through activating AMP-activated protein kinase (AMPK) and inhibiting mechanistic target of rapamycin (mTOR), promoting cellular detoxification and homeostasis. NOB has the potential as a therapeutic agent that leverages the autophagic pathway to mitigate the adverse effects of NPs, suggesting a novel approach for managing NPs toxicity in human intestinal Caco-2 cells.
    Keywords:  Caco‐2 cells; autophagy; nanoplastics (NPs); nobiletin (NOB); oxidative stress
    DOI:  https://doi.org/10.1096/fj.202402761R
  32. J Zhejiang Univ Sci B. 2025 Mar 01. pii: 1673-1581(2025)03-0227-13. [Epub ahead of print]26(3): 227-239
    Autophagy in skeletal muscle dysfunction of chronic obstructive pulmonary disease: implications, mechanisms, and perspectives.
    Xiaoyu Han, Peijun Li, Meiling Jiang, Yuanyuan Cao, Yingqi Wang, Linhong Jiang, Xiaodan Liu, Weibing Wu.
      Skeletal muscle dysfunction is a common extrapulmonary comorbidity of chronic obstructive pulmonary disease (COPD) and is associated with decreased quality-of-life and survival in patients. The autophagy lysosome pathway is one of the proteolytic systems that significantly affect skeletal muscle structure and function. Intriguingly, both promoting and inhibiting autophagy have been observed to improve COPD skeletal muscle dysfunction, yet the mechanism is unclear. This paper first reviewed the effects of macroautophagy and mitophagy on the structure and function of skeletal muscle in COPD, and then explored the mechanism of autophagy mediating the dysfunction of skeletal muscle in COPD. The results showed that macroautophagy- and mitophagy-related proteins were significantly increased in COPD skeletal muscle. Promoting macroautophagy in COPD improves myogenesis and replication capacity of muscle satellite cells, while inhibiting macroautophagy in COPD myotubes increases their diameters. Mitophagy helps to maintain mitochondrial homeostasis by removing impaired mitochondria in COPD. Autophagy is a promising target for improving COPD skeletal muscle dysfunction, and further research should be conducted to elucidate the specific mechanisms by which autophagy mediates COPD skeletal muscle dysfunction, with the aim of enhancing our understanding in this field.
    Keywords:  Autophagy; Chronic obstructive pulmonary disease; Mitochondria; Muscle satellite cell; Skeletal muscle dysfunction
    DOI:  https://doi.org/10.1631/jzus.B2300680
  33. Int J Mol Sci. 2025 Feb 21. pii: 1868. [Epub ahead of print]26(5):
    A Comprehensive Review of Nanoparticle-Based Drug Delivery for Modulating PI3K/AKT/mTOR-Mediated Autophagy in Cancer.
    Md Ataur Rahman, Maroua Jalouli, Sujay Kumar Bhajan, Mohammed Al-Zharani, Abdel Halim Harrath.
      The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathway plays a crucial role in the regulation of autophagy, a cellular mechanism vital for homeostasis through the degradation of damaged organelles and proteins. The dysregulation of this pathway is significantly associated with cancer progression, metastasis, and resistance to therapy. Targeting the PI3K/AKT/mTOR signaling pathway presents a promising strategy for cancer treatment; however, traditional therapeutics frequently encounter issues related to nonspecific distribution and systemic toxicity. Nanoparticle-based drug delivery systems represent a significant advancement in addressing these limitations. Nanoparticles enhance the bioavailability, stability, and targeted delivery of therapeutic agents, facilitating the precise modulation of autophagy in cancer cells. Functionalized nanoparticles, such as liposomes, polymeric nanoparticles, and metal-based nanocarriers, facilitate targeted drug delivery to tumor tissues, minimizing off-target effects and improving therapeutic efficacy. These systems can deliver multiple agents concurrently, enhancing the modulation of PI3K/AKT/mTOR-mediated autophagy and related oncogenic pathways. This review examines advancements in nanoparticle-mediated drug delivery that target the PI3K/AKT/mTOR pathway, emphasizing their contribution to improving precision and minimizing side effects in cancer therapy. The integration of nanotechnology with molecularly targeted therapies presents substantial potential for addressing drug resistance. Future initiatives must prioritize the optimization of these systems to enhance clinical translation and patient outcomes.
    Keywords:  PI3K/AKT/mTOR; autophagy; cancer therapy; drug delivery; nanoparticles; targeted therapy
    DOI:  https://doi.org/10.3390/ijms26051868
  34. Eur Neuropsychopharmacol. 2025 Mar 06. pii: S0924-977X(25)00028-8. [Epub ahead of print]94 24-35
    Chronic mild stress dysregulates autophagy, membrane dynamics, and lysosomal status in frontal cortex and hippocampus of rats.
    Cristina Ulecia-Morón, Álvaro G Bris, Karina S MacDowell, Pilar Cerveró-García, José L M Madrigal, Borja García-Bueno, Marta P Pereira, Juan C Leza, Javier R Caso.
      Inflammation has been related to major depressive disorder pathophysiology. Autophagy, a degradative pathway regulating inflammation and immunity, has emerged as a potential contributor. Among others, we characterized, in frontal cortex (FC) and hippocampus (Hp), autophagy markers (upregulations in mTOR, ATG7, and ATG 16L1, and downregulations in ULK1, BECLIN1, phospho-SQSTM1, ATG3, ATG12, and ATG 16L1), effectors of the endosomal sorting complexes required for transport (overexpression in HRS, VPS37A, CHMP6, and GALECTIN 3, and downregulations in STAM2, TSG101, VPS28, VPS37A, CHMP5, VPS4B, and GALECTIN 9), and lysosomal proteins (LAMP1, LAMP2A, MANNOSE RECEPTOR, HSC70, HSP70, CATHEPSIN D and B, and CYSTATIN C, whose variations are dependent on lysosomal nature and brain region) of male rats exposed to chronic mild stress, a model of depression, compared to control rats. Results indicate that chronic stress alters protein expression of autophagy and the endosomal sorting complexes required for transport markers in a region-specific manner, plus increases lysosomal presence, oppositely modulating lysosomal proteins in each structure. Additionally, astrocytes seemed to exert an essential role in the regulation of the autophagy adaptor SQSTM1/p62. In conclusion, stress-induced protein disruptions in these pathways highlight their differential modulation after chronic stress exposure and their potential role in maintaining brain homeostasis during the stress response, making them promising targets for new therapeutic strategies in stress-related pathologies.
    Keywords:  Autophagy; Chronic mild stress; ESCRT; Lysosome; SQSTM1/p62
    DOI:  https://doi.org/10.1016/j.euroneuro.2025.02.005
  35. Life Sci. 2025 Mar 10. pii: S0024-3205(25)00187-0. [Epub ahead of print]369 123553
    Polymyxin B induces pigmentation by upregulating ATG2A-ERK/CREB-MITF-PMEL17 signaling axis.
    Miao-Qing Zhang, Zheng-Hao Wang, Dan-Qing Song, Jing-Pu Zhang.
      Polymyxin B serves as the last line of defense in treating multidrug-resistant Gram-negative bacterial infections. However, its distinctive side effect of hyperpigmentation significantly impacts patients' psychological well-being and treatment adherence. Currently, the underlying mechanism of polymyxin B-induced pigmentation remains to be incompletely investigated. This study aims to explore the correlation between polymyxin B-induced pigmentation and autophagy in zebrafish and melanoma cells. Comparative analysis between polymyxin B and its analog polymyxin E reveals opposite effects of the two polymyxins on PMEL17 expression and autophagic flux. Polymyxin B increases PMEL17 expression, correlating with elevated LC3B-II/I level and inhibition of autolysosomal degradation activity, while polymyxin E exerts the contrary effects. RNA-seq analysis of autophagy genes identifies a significant upregulation of ATG2A expression induced by polymyxin B. Moreover, polymyxin B, dependent on ATG2A, promotes MITF overexpression through the LC3B-II/pERK/pCREB pathway, subsequently enhancing PMEL17 expression. This study elucidates the mechanism linking polymyxin B-induced pigmentation and autophagy, demonstrating that polymyxin B causes the accumulation of PMEL17 within autophagosomes and inhibits its autophagic degradation, suggesting that autophagosomes may transform into melanosomes. These findings further contribute to the theoretical basis for autophagy regulating melanin synthesis, highlighting the multifaceted functions of autophagic proteins beyond degradation within autolysosomes.
    Keywords:  ATG2A; Autophagy; Melanoma cells; PMEL17; Pigmentation; Polymyxin B
    DOI:  https://doi.org/10.1016/j.lfs.2025.123553
  36. J Transl Med. 2025 Mar 10. 23(1): 297
    mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS.
    Jacob Bar-Tana.
      Post-acute SarS-Cov2 (PASC), Myalgia encephalomyelitis/Chronic fatigue syndrome (ME/CFS) and Post-acute infection syndrome (PAIS) consist of chronic post-acute infectious syndromes, sharing exhaustive fatigue, post exertional malaise, intermittent pain, postural tachycardia and neuro-cognitive-psychiatric dysfunction. However, the concerned shared pathophysiology is still unresolved in terms of upstream drivers and transducers. Also, risk factors which may determine vulnerability/progression to the chronic phase still remain to be defined. In lack of drivers and a cohesive pathophysiology, the concerned syndromes still remain unmet therapeutic needs. 'mTORC1 Syndrome' (TorS) implies an exhaustive disease entity driven by sustained hyper-activation of the mammalian target of rapamycin C1 (mTORC1), and resulting in a variety of disease aspects of the Metabolic Syndrome (MetS), non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, some cancers, neurodegeneration and other [Bar-Tana in Trends Endocrinol Metab 34:135-145, 2023]. TorS may offer a cohesive insight of PASC, ME/CFS and PAIS drivers, pathophysiology, vulnerability and treatment options.
    Keywords:  Mammalian target of rapamycin C1 (mTORC1); Myalgia encephalomyelitis/chronic fatigue syndrome (ME/CFS); Post-acute SarS-Cov2 (PASC); Post-acute infection syndrome (PAIS); mTORC1 syndrome (TorS)
    DOI:  https://doi.org/10.1186/s12967-025-06220-z
  37. J Cell Sci. 2025 Mar 01. pii: JCS263652. [Epub ahead of print]138(5):
    Disruption of ER-mitochondria contact sites induces autophagy-dependent loss of P-bodies through the Ca2+-CaMKK2-AMPK pathway.
    Nikhil More, Jomon Joseph.
      P-bodies (PBs) and stress granules (SGs) are conserved, non-membranous cytoplasmic condensates of RNA-protein complexes. PBs are implicated in post-transcriptional regulation of gene expression through mRNA decay, translational repression and/or storage. Although much is known about the de novo formation of PBs and SGs involving liquid-liquid phase separation through multiple protein-protein and protein-RNA interactions, their subcellular localization and turnover mechanisms are less understood. Here, we report the presence of a subpopulation of PBs and SGs that are in proximity to ER-mitochondria contact sites (ERMCSs) in mammalian cells. Disruption of ERMCSs, achieved through depletion of ER-mitochondria tethering proteins, leads to the disappearance of PBs but not SGs. This effect can be reversed by inhibiting autophagy through both genetic and pharmacological means. Additionally, we find that the disruption of ERMCSs leads to cytosolic Ca2+-induced activation of CaMKK2 and AMP-activated protein kinase (AMPK), ultimately resulting in an autophagy-dependent decrease in PB abundance. Collectively, our findings unveil a mechanism wherein disturbances in ERMCSs induce autophagy-dependent loss of PBs via activation of the Ca2+-CaMKK2-AMPK pathway, thus potentially linking the dynamics and functions of ERMCS with post-transcriptional gene regulation.
    Keywords:  Autophagy; CaMKK2; ER–mitochondria contact sites; P-bodies; Stress granules
    DOI:  https://doi.org/10.1242/jcs.263652
  38. Front Cell Dev Biol. 2025 ;13 1551003
    Ferritinophagy: multifaceted roles and potential therapeutic strategies in liver diseases.
    Kejia Wu, Wei Zhao, Zeyu Hou, Weigang Zhang, Lei Qin, Junyi Qiu, Daobin Wang, Lin Zhuang, Xiaofeng Xue, Ding Sun.
      Ferritinophagy, the selective autophagic degradation of ferritin to release iron, is emerging as a critical regulator of iron homeostasis and a key player in the pathogenesis of various liver diseases. This review comprehensively examines the mechanisms, regulation, and multifaceted roles of ferritinophagy in liver health and disease. Ferritinophagy is intricately regulated by several factors, including Nuclear Receptor Coactivator 4 (NCOA4), Iron regulatory proteins and signaling pathways such as mTOR and AMPK. These regulatory mechanisms ensure proper iron utilization and prevent iron overload, which can induce oxidative stress and ferroptosis. In liver diseases, ferritinophagy exhibits dual roles. In liver fibrosis, promoting ferritinophagy in hepatic stellate cells (HSCs) can induce cell senescence and reduce fibrosis progression. However, in non-alcoholic fatty liver disease (NAFLD), chronic ferritinophagy may exacerbate liver injury through iron overload and oxidative stress. In hepatocellular carcinoma (HCC), ferritinophagy can be harnessed as a novel therapeutic strategy by inducing ferroptosis in cancer cells. Additionally, ferritinophagy is implicated in drug-induced liver injury and sepsis-associated liver damage, highlighting its broad impact on liver pathology. This review also explores the crosstalk between ferritinophagy and other selective autophagy pathways, such as mitophagy and lipophagy, which collectively influence cellular homeostasis and disease progression. Understanding these interactions is essential for developing comprehensive therapeutic strategies targeting multiple autophagy pathways. In summary, ferritinophagy is a complex and dynamic process with significant implications for liver diseases. This review provides an in-depth analysis of ferritinophagy's regulatory mechanisms and its potential as a therapeutic target, emphasizing the need for further research to elucidate its role in liver health and disease.
    Keywords:  HCC; NAFLD; autophagy; ferritinophagy; ferroptosis; liver fibrosis
    DOI:  https://doi.org/10.3389/fcell.2025.1551003
  39. Int Immunopharmacol. 2025 Mar 10. pii: S1567-5769(25)00388-1. [Epub ahead of print]152 114398
    The transcription factor XBP1 regulates mitochondrial remodel and autophagy in spontaneous abortion.
    Weihua He, Yating Zhao, Lijun Yin, Qiangxing Du, Wenfen Ren, Liwei Mao, Aixia Liu, Dimin Wang, Jianhua Qian.
       PURPOSE: Spontaneous abortion (SA) remains a clinical challenge in early pregnancy. It has been reported that endoplasmic reticulum stress (ERS) is implicated in pregnancy-related complications. However, the precise mechanistic role of ERS in SA pathogenesis remains elusive. This study aims to explore the therapeutic potential of targeting ERS-related decidual dysfunction in SA.
    METHODS: An ERS model was established in both decidualized stromal cells (DSCs) and pregnant mice through tunicamycin (Tu) administration. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were performed to determine the interaction between XBP1s and the transcription factor binding site (TFBS) of tumor necrosis factor receptor-associated factor 6 (TRAF6). Mitochondrial membrane potential (MMP) and mitochondrial function were assessed using JC-1 and TMRM staining following ERS induction in DSCs. The effects of XBP1s inhibitors on mitochondrial metabolism and autophagy were evaluated through RT-qPCR, Western blotting, RNA-Seq, TUNEL assays, ROS and MitoSOX detection, and histological analyses in Tu-treated DSCs and SA patients. STF-083010 (STF) or shXBP1 was utilized to assess the inhibitory effects of X-box binding protein 1 (XBP1s) on DSC function both in vitro and in vivo.
    RESULTS: We observed significant upregulation of XBP1s in decidual tissues from SA patients and Tu-exposed DSCs. Tu exposure significantly increased the proportion of TUNEL-positive cells and upregulated pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-18) in DSCs. XBP1s inhibition via shXBP1 or pharmacological inhibitor STF attenuated Tu-induced apoptosis and inflammatory cytokine expression. Notably, STF or shXBP1 treatment enhanced MMP and upregulated LC3-II expression in Tu-treated DSCs, indicating autophagy activation.Intriguingly, chloroquine (CQ)-mediated autophagy suppression exacerbated apoptosis in STF/Tu-co-treated DSCs, suggesting that XBP1s inhibition confers cytoprotection through autophagy induction. Mechanistically, XBP1s directly bound to the TFBS of TRAF6, a ubiquitin E3 ligase. TRAF6 overexpression exacerbated mitochondrial dysfunction and apoptosis while suppressing autophagy via inhibition of mTORC2/Akt pathway in Tu-treated DSCs.
    CONCLUSION: XBP1s inhibition restored mitochondrial homeostasis and promoted autophagy by modulating the TRAF6/mTORC2 axis under ERS conditions, providing novel mechanistic insights into SA pathogenesis and potential therapeutic targets.
    Keywords:  Autophagy; ERS; Mitochondrial function; SA; XBP1
    DOI:  https://doi.org/10.1016/j.intimp.2025.114398
  40. Eur J Med Chem. 2025 Mar 04. pii: S0223-5234(25)00241-7. [Epub ahead of print]289 117476
    Mechanisms and therapeutic strategies for NLRP3 degradation via post-translational modifications in ubiquitin-proteasome and autophagy lysosomal pathway.
    Kaiyue Su, Minghai Tang, Jie Wu, Neng Ye, Xueqin Jiang, Min Zhao, Ruijia Zhang, Xiaoying Cai, Xinlu Zhang, Na Li, Jing Peng, Lei Lin, Wenshuang Wu, Haoyu Ye.
      The NLRP3 inflammasome is crucial for immune responses. However, its overactivation can lead to severe inflammatory diseases, underscoring its importance as a target for therapeutic intervention. Although numerous inhibitors targeting NLRP3 exist, regulating its degradation offers an alternative and promising strategy to suppress its activation. The degradation of NLRP3 is primarily mediated by the proteasomal and autophagic pathways. The review not only elaborates on the traditional concepts of ubiquitination and NLRP3 degradation but also investigates the important roles of indirect regulatory modifications, such as phosphorylation, acetylation, ubiquitin-like modifications, and palmitoylation-key post-translational modifications (PTMs) that influence NLRP3 degradation. Additionally, we also discuss the potential targets that may affect NLRP3 degradation during the proteasomal and autophagic pathways. By unraveling these complex regulatory mechanisms, the review aims to enhance the understanding of NLRP3 regulation and its implications for developing therapeutic strategies to combat inflammatory diseases.
    Keywords:  Inhibitors; NLRP3; Post-translational modifications (PTMs); Protein degradation; Ubiquitination
    DOI:  https://doi.org/10.1016/j.ejmech.2025.117476
  41. J Neuroinflammation. 2025 Mar 07. 22(1): 68
    Microglial progranulin differently regulates hypothalamic lysosomal function in lean and obese conditions via cleavage-dependent mechanisms.
    Chae Beom Park, Chan Hee Lee, Gil Myoung Kang, Se Hee Min, Min-Seon Kim.
      Progranulin (PGRN) is a secretory precursor protein composed of 7.5 granulins (GRNs). Mutations in the PGRN-encoding gene Grn have been associated with neurodegenerative diseases. In our previous study, we found that Grn depletion in microglia disrupted glucose metabolism in mice fed a normal chow diet (NCD) but prevented the development of obesity in mice on a high-fat diet (HFD). Given that PGRN regulates lysosomal functions, we investigated lysosomal changes in the hypothalamus of mice with microglia-specific Grn depletion. Here we report that microglia-specific Grn depletion affects the lysosomes of hypothalamic proopiomelanocortin (POMC) neurons and microglia in diet-dependent fashion. Under NCD conditions, microglial Grn depletion led to increased lysosome mass, reduced lysosomal degradative capacity, and accumulation of lipofuscin and cytoplasmic TDP-43 in hypothalamic cells, indicative of lysosomal stress and dysfunction. In contrast, under HFD conditions, the absence of microglial Grn suppressed HFD-induced hypothalamic lysosomal stress. In cultured hypothalamic neurons and microglia, PGRN treatment enhanced lysosomal function, an effect inhibited by PGRN cleavage but restored when its cleavage was blocked. Since HFD feeding promotes the cleavage of hypothalamic PGRN into multi-GRNs and GRNs, the diet-dependent lysosomal changes observed in microglial Grn-depleted mice may be linked to PGRN cleavage. We also demonstrated that intracerebroventricular injection of bafilomycin, which induces lysosomal stress, resulted in microglial activation, inflammation, disrupted POMC neuronal circuitry, and impaired leptin signaling in the hypothalamus-common features of obesity. Our results indicate that microglial PGRN plays an important role in maintaining hypothalamic lysosomal function under healthy diet conditions, whereas increased cleavage of microglial PGRN in states of overnutrition disrupts hypothalamic lysosomal function, thereby fostering hypothalamic inflammation and obesity.
    Keywords:  Granulin; Hypothalamus; Lysosome; Obesity; Progranulin
    DOI:  https://doi.org/10.1186/s12974-025-03370-1
  42. J Cell Sci. 2025 Mar 07. pii: jcs.263852. [Epub ahead of print]
    ATG9A vesicles are a subtype of intracellular nanovesicle.
    Mary Fesenko, Daniel J Moore, Peyton Ewbank, Elizabeth Courthold, Stephen J Royle.
      Cells are filled with thousands of vesicles, which mediate protein transport and ensure homeostasis of the endomembrane system. Distinguishing these vesicles functionally and molecularly represents a major challenge. Intracellular nanovesicles (INVs) are a large class of transport vesicles that likely comprises of multiple subtypes. Here, we define the INV proteome and find that it is molecularly heterogeneous, and enriched for transmembrane cargo molecules including integrins, transporters, and ATG9A, a lipid scramblase associated with autophagy. ATG9A is known to reside in 'ATG9A vesicles': small vesicles that contribute to autophagosome formation. Using in-cell vesicle capture assays we found that ATG9A, as well as other ATG9A vesicle cargos, were in INVs. Quantitative analysis showed that virtually all ATG9A vesicles are INVs, but that only ∼20% of INVs are ATG9A vesicles, suggesting that ATG9A vesicles are in fact a subtype of INV, which we term ATG9A-flavor INVs. Finally, we show that perturbing ATG9A-flavor INVs impaired the autophagy response induced by starvation.
    Keywords:  Autophagy; Cargo; Membrane traffic; Proteomics; Transport vesicle
    DOI:  https://doi.org/10.1242/jcs.263852
  43. Zhen Ci Yan Jiu. 2025 Feb 25. pii: 1000-0607(2025)02-0204-06. [Epub ahead of print]50(2): 204-209
    Research progress on the mechanisms of acupuncture in improving ischemic stroke through autophagy.
    Yu Wang, Yi-Ning Dai, Xiao-Jing Guo, Miao Hua, Li Zhang.
      Stroke is a major disease with high incidence, disability rate, and mortality worldwide. In recent years, a large number of studies have comfirmed that acupuncture treatment for ischemic stroke is closely related to the regulation of autophagy mechanisms. This article summarizes the literature in recent years, discusses the effects of acupuncture on the degradation pathways mediated by autophagosomes, the expression of autophagy-related proteins, autophagy-related pathways, and the impact of mitophagy, and further explores the mechanisms of acupuncture in regulating autophagy to improve ischemic stroke, providing new ideas and schemes for clinical treatment.
    Keywords:  Acupuncture; Autophagy; Ischemic stroke; Mechanism; Review
    DOI:  https://doi.org/10.13702/j.1000-0607.20230791
  44. Crit Rev Oncol Hematol. 2025 Mar 12. pii: S1040-8428(25)00088-5. [Epub ahead of print] 104700
    The Dual Role of Chaperone-mediated Autophagy in the Response and Resistance to Cancer Immunotherapy.
    Mohammadreza Saberiyan, Sarah Gholami, Mahsa Ejlalidiz, Mohammadsadegh Rezaeian Manshadi, Parisa Anoorabadi, Michael R Hamblin.
      Cancer immunotherapy has become a revolutionary strategy in oncology, utilizing the host immune system to fight malignancies. Notwithstanding major progress, obstacles such as immune evasion by tumors and the development of resistance still remain. This manuscript examines the function of chaperone-mediated autophagy (CMA) in cancer biology, focusing on its effects on tumor immunotherapy response and resistance. CMA is a selective degradation mechanism for cytosolic proteins, which is crucial for sustaining cellular homeostasis and regulating immune responses. By degrading specific proteins, CMA can either facilitate tumor progression in stressful conditions, or promote tumor suppression by removing oncogenic factors. This double-edged sword highlights the complexity of CMA in cancer progression and its possible effect on treatment results. Here we clarify the molecular mechanisms by which CMA can regulate the immune response and its possible role as a therapeutic target for improving the effectiveness of cancer immunotherapy.
    Keywords:  (cGAS)-STING pathway; Immune checkpoint inhibitors; Immune evasion; Resistance mechanisms; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104700
  45. EMBO Mol Med. 2025 Mar 07.
    Chaperone-mediated autophagy regulates the metastatic state of mesenchymal tumors.
    Xun Zhou, Eva Berenger, Yong Shi, Vera Shirokova, Elena Kochetkova, Tina Becirovic, Boxi Zhang, Vitaliy O Kaminskyy, Yashar Esmaeilian, Kayoko Hosaka, Cecilia Lindskog, Per Hydbring, Simon Ekman, Yihai Cao, Maria Genander, Marcin Iwanicki, Erik Norberg, Helin Vakifahmetoglu-Norberg.
      Tumors often recapitulate programs to acquire invasive and dissemination abilities, during which pro-metastatic proteins are distinctively stabilized in cancer cells to drive further progression. Whether failed protein degradation affects the metastatic programs of cancer remains unknown. Here, we show that the human cancer cell-specific knockout (KO) of LAMP-2A, a limiting protein for chaperone-mediated autophagy (CMA), promotes the aggressiveness of mesenchymal tumors. Deficient CMA resulted in widespread tumor cell dissemination, invasion into the vasculature and cancer metastasis. In clinical samples, metastatic lesions showed suppressed LAMP-2A expression compared to primary tumors from the same cancer patients. Mechanistically, while stimulating TGFβ signaling dampens LAMP-2A levels, genetic suppression of CMA aggravated TGFβ signaling in cancer cells and tumors. Conversely, pharmacological inhibition of TGFβ signaling repressed the growth of LAMP-2A KO-driven tumors. Furthermore, we found that multiple EMT-driving proteins, such as TGFβR2, are degraded by CMA. Our study demonstrates that the tumor suppressive function of CMA involves negative regulation of TGFβ-driven EMT and uncovers a mechanistic link between CMA and a major feature of metastatic invasiveness.
    Keywords:  Cancer; Chaperone-mediated Autophagy; EMT; Metastasis; TGFβ
    DOI:  https://doi.org/10.1038/s44321-025-00210-w
  46. Hepatol Commun. 2025 Apr 01. pii: e0654. [Epub ahead of print]9(4):
    Amphisome plays a role in HBV production and release through the endosomal and autophagic pathways.
    Jia Li, Thekla Kemper, Ruth Broering, Yong Lin, Xueyu Wang, Mengji Lu.
       BACKGROUND: Autophagic and endosomal pathways coordinately contribute to HBV virions and subviral particles (SVPs) production. To date, limited evidence supports that HBV and exosomes have a common pathway for their biogenesis and secretion. The final steps of HBV production and release have not yet been well studied.
    METHODS: We examined the production and release of HBV virions and SVPs by using GW4869 (N,N'-Bis[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-3,3'-pht hal amide dihydrochloride), a small molecule inhibiting ceramide-mediated inward membrane budding. Neutral sphingomyelinase, the target of GW4869, and RAB27A and -B,  2 small GTPases involved in exosome release control, were silenced using gene silencing to confirm the results obtained. Western blot, immunofluorescence staining, and confocal microscopy were applied.
    RESULTS: GW4869 inhibited HBV virion release, causing their accumulation along with SVPs in hepatocytes. This triggered cellular endoplasmic reticulum stress, leading to protein kinase B-mechanistic target of rapamycin kinase signaling pathway inactivation. GW4869 treatment increased autophagosome formation and impaired autophagic degradation by blocking autophagosome-lysosome fusion. Consequently, HBsAg is increasingly localized to autophagosomes and late endosomes/multivesicular bodies. Silencing neutral sphingomyelinase yielded consistent results. Similarly, RAB27A silencing inhibited HBV virion and SVP secretion, causing their accumulation within hepatoma cells. Notably, GW4869 treatment, as well as RAB27A and -B silencing, increased the presence of LC3+CD63+HBsAg+ complexes.
    CONCLUSIONS: Our results demonstrate the involvement of the autophagosome-late endosome/multivesicular bodies-exosome axis in regulating HBV production and release, highlighting amphisomes as a potential platform for HBV release.
    DOI:  https://doi.org/10.1097/HC9.0000000000000654
  47. J Immunol. 2025 Feb 01. 214(2): 265-277
    Ammonium chloride mitigates the amplification of fish virus by blocking autophagy-dependent replication.
    Dan-Dan Chen, Jia-Xin Zhang, Zhuo-Cong Li, Can Zhang, Xiao Xu, Bao-Jie Cui, Na Xu, Yang-Yang Wang, Chu-Jing Zhou, Li Zhou, Long-Feng Lu, Shun Li.
      Ammonia fertilizer, primarily composed of ammonium chloride, is widely used in pond fish farming throughout Asia. Despite the belief that it possesses antiviral properties, the underlying mechanisms remain unclear. Ammonium chloride (NH4Cl) has been demonstrated to act as a potent inhibitor of autophagy, which is used by many fish viruses to promote their proliferation during infection. It was therefore hypothesized that the antiviral effect of ammonia fertilizers was likely due to the inhibition of autophagy in viruses. The present study sought to evaluate the antiviral effect of NH4Cl in a model of several fish cells and zebrafish. The findings demonstrated that the administration of NH4Cl after viral infection inhibited the proliferation of a variety of fish viruses, encompassing both DNA and RNA viruses. Further studies have indicated that NH4Cl obstructed autophagy-dependent virus proliferation of spring viremia of carp virus (SVCV) by inhibiting autophagic flux. The molecular mechanism revealed that SVCV contributed to the polyubiquitination of interferon regulatory factor 3 (IRF3) and promoted the degradation of IRF3 through cargo receptor sequestosome 1 (SQSTM1/p62)-mediated selective autophagy. However, NH4Cl was observed to inhibit SVCV-mediated selective autophagy of IRF3, thereby facilitating the production of interferon. Furthermore, the SVCV N protein was of critical importance in this process. Nevertheless, NH4Cl impeded this degradation process by inhibiting the autophagy pathway. The study found that NH4Cl was highly efficacious in controlling fish virus infection both in vivo and in vitro. It can therefore be concluded that the antiviral effect of ammonia fertilizers was, at least in part, due to the inhibition of viral autophagy.
    Keywords:  IRF3; P62; ammonium chloride; autophagy; fish virus
    DOI:  https://doi.org/10.1093/jimmun/vkae012
  48. J Cell Mol Med. 2025 Mar;29(5): e70488
    Danuglipron Ameliorates Pressure Overload-Induced Cardiac Remodelling Through the AMPK Pathway.
    Pan Wang, Zhen Guo, Chun-Yan Kong, Yu-Lan Ma, Ming-Yu Wang, Xin-Ru Zhang, Zheng Yang.
      Cardiac remodelling, a pathological process induced by various cardiovascular diseases, remains a significant challenge in clinical practice. Here, we investigate the potential of Danuglipron (PF-06882961, PF), a novel oral glucagon-like peptide-1 (GLP-1) receptor agonist, in alleviating pressure overload (PO)-induced cardiac hypertrophy and fibrosis. Using both in vivo and in vitro models, we demonstrate that PF treatment (1 mg/kg/day, orally for 8 weeks) significantly attenuates aortic banding-induced cardiac dysfunction and pathological remodelling in mice. Mechanistically, we show that PF mitigates apoptotic responses and enhances autophagy by promoting AMPK phosphorylation and increasing HSP70 expression. Notably, the cardioprotective effects of PF are abolished in AMPKα2 knockout mice, with no observable increase in HSP70 levels. Our findings reveal a previously unrecognised role of PF in cardiac protection, mediated through the AMPKα-HSP70 signalling pathway, and suggest its potential as a therapeutic strategy for PO-induced cardiac remodelling.
    Keywords:  Danuglipron (PF); GLP‐1 receptor agonist; HSP70; autophagy; cardiac remodelling
    DOI:  https://doi.org/10.1111/jcmm.70488
  49. Phytomedicine. 2025 Mar 01. pii: S0944-7113(25)00233-8. [Epub ahead of print]140 156593
    Liensinine overcomes EGFR-TKI resistance in lung adenocarcinoma through DRP1-mediated autophagy.
    Yuling Chen, Chenying Shu, Zhaowei Yan, Saiqun Zhang, Weijie Zhang, Jian Zhao, Anqi Wang, Jianjun Li, Yuanyuan Zeng, Jianjie Zhu, Jian-An Huang, Zeyi Liu.
       INTRODUCTION: Persistent upregulation of autophagy contributes to tumour cells' resistance to EGFR-TKI therapy, and hence, inhibiting autophagy could be a valuable strategy for overcoming such resistance.
    OBJECTIVES: This study investigated the effects of liensinine in EGFR-TKI resistant lung adenocarcinoma (LUAD) and to explore the underlying mechanism.
    METHODS: CCK-8 assay, colony formation, EdU assay and apoptosis assays were conducted for investigating the effect of EGFR-TKI and liensinine combination treatment in LUAD. Furthermore, autophagic flux were detected by western blot, fluorescence assays and TEM. In addition, by employing a DARTS approach, a CETSA assay, and SPR analysis, we identified DRP1 as a target of liensinine. Finally, by establishing a xenograft model of the disease, the impact of combination treatment in vivo was assessed.
    RESULT: In vitro and in vivo experiments revealed that the novel autophagy inhibitor liensinine enhanced the sensitivity of LUAD to EGFR-TKIs. This effect was achieved by inhibiting autophagic flux. We then examined whether liensinine inhibits autophagic flux through the impairment of autophagosome and autolysosome degradation. Furthermore, we identified DRP1 as a target of liensinine. The activation of DRP1 by liensinine through dephosphorylation at Ser637 promotes the accumulation of autophagosomes and autolysosomes while simultaneously blocking autophagic flux, thereby enhancing the cancer cell-killing effects of EGFR-TKIs.
    CONCLUSIONS: Our study validated the efficacy of liensinine in overcoming EGFR-TKI resistance and elucidated the mechanism underlying liensinine's inhibition of autophagy.
    Keywords:  Autophagy; Drug resistance; EGFR-TKI; Liensinine; Lung adenocarcinoma
    DOI:  https://doi.org/10.1016/j.phymed.2025.156593
  50. Commun Biol. 2025 Mar 13. 8(1): 433
    Arthropod autophagy molecules facilitate Anaplasma phagocytophilum infection of Ixodes scapularis tick cells.
    Jeremy W Turck, Hameeda Sultana, Girish Neelakanta.
      Ixodes scapularis ticks transmit several medically important pathogens including Anaplasma phagocytophilum to humans and animals. In this study, we provide evidence that A. phagocytophilum modulates autophagy molecules for its survival in tick cells. qRT-PCR analysis revealed that A. phagocytophilum infection results in the upregulation of tyrosine phosphatase, shp-2, and serine/threonine-protein kinase, mTOR, in ticks and tick cells. RNAi-mediated knockdown of shp-2 or functional blocking with SHP-2 inhibitor resulted in significantly increased bacterial burden and reduced phospho-mTOR levels in A. phagocytophilum-infected tick cells. In addition, treatment of A. phagocytophilum-infected tick cells with rapamycin (mTOR inhibitor) resulted in significantly increased bacterial burden and reduced phospho-mTOR levels. Furthermore, expression of autophagy molecules such as atg14 and ulk1 were noted to be upregulated in both A. phagocytophilum-infected unfed ticks and tick cells. RNAi-mediated silencing of atg14 or ulk1 affected bacterial growth in tick cells. Collectively, these results not only indicate distinct host and pathogen responses in tick-A. phagocytophilum interactions but also suggest that this bacterium modulates autophagy molecules for its survival in ticks.
    DOI:  https://doi.org/10.1038/s42003-025-07859-6
  51. Free Radic Biol Med. 2025 Mar 10. pii: S0891-5849(25)00160-1. [Epub ahead of print]
    5-Methoxytryptophan Attenuates Oxidative Stress-Induced Downregulation of PINK1 and Mitigates Mitochondrial Damage and Apoptosis in Cardiac Myocytes.
    Chii-Ming Lee, Tung-Chun Chien, Juo-Shan Wang, Yu-Wei Chen, Chin-Yu Chen, Chen-Chin Kuo, Liang-Ting Chiang, Kenneth K Wu, Wan-Tseng Hsu.
      Mitochondrial dysfunction is a hallmark in the pathogenesis of various cardiovascular diseases. 5-Methoxytryptophan (5-MTP), an intrinsic amino acid metabolite, exerts cardioprotective effects potentially through the preservation of mitochondrial integrity. This study investigates the mechanisms and contexts in which 5-MTP positively impacts mitochondrial function using cultured human ventricular cardiomyocytes (HCMs) and HL-1 cardiac cells subjected to oxidative stress (OS). We first demonstrated that 5-MTP up-regulates the expression of PINK1, a key regulator of mitochondrial homeostasis. PINK1 knockdown attenuated the beneficial effects of 5-MTP on cardiomyocyte apoptosis. Furthermore, in cells exposed to OS, 5-MTP pretreatment led to a notable decrease in mitochondrial superoxide generation. Fluorescence imaging and network analysis showed that 5-MTP preserved mitochondrial membrane potential and enhanced mitochondrial network integrity. The reduction in the phosphorylation of dynamin-related protein 1, which is involved in mitochondrial fission, uncovered the role of 5-MTP in maintaining mitochondrial dynamics. Notably, 5-MTP attenuated OS-induced mitophagy, as evidenced by reduced mitophagy detection dye fluorescence and lower mitochondrial Parkin levels, suggesting that mechanisms beyond the PINK1/Parkin pathway are involved. Restoration of AKT phosphorylation and reduced mitochondrial Bax localization further revealed an additional pathway contributing to mitochondrial protection. Moreover, 5-MTP attenuated pro-apoptotic Bax levels and enhanced PINK1 expression in a rat model of ischemic cardiomyopathy, corroborating its cardioprotective role. Collectively, these findings demonstrate that 5-MTP mitigates mitochondrial dysfunction by integrating the roles of PINK1, AKT, and Bax, offering potential as a therapeutic agent to enhance cellular resilience in OS-driven mitochondrial damage.
    Keywords:  5-Methoxytryptophan; AKT; Bax; PINK1; apoptosis; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.03.010
  52. JCI Insight. 2025 Mar 11. pii: e189817. [Epub ahead of print]
    Anoctamin5 deficiency enhances ATG9A-dependent autophagy, inducing osteogenesis and gnathodiaphyseal dysplasia-like bone formation.
    Shuai Zhang, Shengnan Wang, Sirui Liu, Xiu Liu, Mingyue Zhang, Huichong Xu, Xiaoyu Wang, Hongyu Li, Ying Hu.
      Mutations in the anoctamin5 (ANO5) gene can lead to musculoskeletal disorders, with monoallelic (autosomal dominant) mutations typically presenting as skeletal abnormalities known as Gnathodiaphyseal dysplasia (GDD). Clinically, GDD is characterized by thickened cortices of long bones and mandibles, narrowed medullary cavities, and increased bone fragility. While autophagy is necessary in regulating bone formation, the specific relationship between ANO5 and autophagy remains poorly understood. In this study, we demonstrated that Ano5 deficiency activates autophagy in mouse cranial osteoblasts (mCOBs), leading to enhanced osteogenic capacity in Ano5-/- mCOBs. The application of 3-Methyladenine (3-MA) and chloroquine (CQ) reversed the excessive osteogenesis observed in Ano5-/- mCOBs. Further analysis revealed that Ano5 deficiency upregulates the expression of ATG9A, and silencing ATG9A significantly reduces both autophagy and osteogenic activity in Ano5-/- mCOBs. Additionally, the AMP-activated protein kinase (AMPK) was found to regulate ATG9A positively, and inhibiting AMPK reduced ATG9A expression, which in turn mitigated excessive osteogenesis of Ano5-/- mCOBs. Moreover, in vivo experiments confirmed that treatment with 3-MA alleviates the bone phenotype abnormalities in Ano5-/- mice. These findings suggest that Ano5 negatively regulates autophagy, contributing to illuminate pathogenesis of GDD. Meanwhile, this research highlights potential therapeutic strategies targeting autophagy to pave the way for the clinical manifestations of GDD.
    Keywords:  Autophagy; Bone biology; Bone disease; Genetics
    DOI:  https://doi.org/10.1172/jci.insight.189817
  53. Front Immunol. 2025 ;16 1526961
    Ferroptosis and cuproptosis in periodontitis: recent biological insights and therapeutic advances.
    Tengyi Zheng, Fumiao Lu, Peihang Wu, Yangan Chen, Rongxin Zhang, Xin Li.
      Periodontitis is a significant global public health issue associated with the onset and progression of various systemic diseases, thereby requiring additional research and clinical attention. Although ferroptosis and cuproptosis have emerged as significant areas of research in the medical field, their precise roles in the pathogenesis of periodontitis remain unclear. We aim to systematically summarize the current research on ferroptosis and cuproptosis in periodontal disease and investigate the roles of glutathione pathway and autophagy pathway in connecting ferroptosis and cuproptosis during periodontitis. Further, we propose that a homeostatic imbalance of copper and iron, driven by periodontal pathogens, may contribute to elevated periodontal oxidative stress, representing a potential unifying link between ferroptosis and cuproptosis involved in periodontitis. This article presents a comprehensive overview of the molecular mechanisms underlying ferroptosis and cuproptosis in periodontitis, offering novel theoretical insights into its pathogenesis and potential therapeutic targets.
    Keywords:  autophagy; cuproptosis; ferroptosis; glutathione; oxidative stress; periodontitis
    DOI:  https://doi.org/10.3389/fimmu.2025.1526961
  54. Mol Plant Microbe Interact. 2025 Mar 10.
    The Alternaria alternata Mip1/RAPTOR Mediates Virulence by Regulating Toxin Production and Autophagy.
    Yu-Ling Huang, Kuang-Ren Chung, Pei-Ching Wu.
      The necrotrophic pathogen Alternaria alternata produces a host-selective toxin to attack its host plants. This study characterized the crucial function of the Mip1/RAPTOR ortholog (AaMip1) in toxin production and autophagy formation. AaMip1 physically interacts with the Target of Rapamycin (Tor) protein. In response to nitrogen starvation and H2O2, AaMip1 binds to Tor and triggers autophagy and oxidative stress detoxification. Deleting the AaMip1 gene resulted in a ΔAaMip1 strain that increased sensitivity to various oxidants, decreased the expression of two oxidative-stress-response genes, AaYap1 and AaNoxA, and had lower catalase activity than the wild type. ΔAaMip1 produced lower levels of ACT toxin than the wild type after a 7-day incubation; however, ΔAaMip1 produced tricycloalternarene mycotoxins but not ACT after 21 days. The reduction of ΔAaMip1 virulence in the host plant is due to low ACT production, defective H2O2 detoxification, impaired autophagy, and slow growth during invasion. However, AaMip1 plays a negative role in maintaining cell wall integrity and lipid body accumulation. ΔAaMip1 had thicker cell walls and emitted brighter red fluorescence after staining with the cell-wall disrupting agents Congo red and calcofluor white. ΔAaMip1 was more resistant to these compounds than the wild type under nutrient-rich conditions. The observed defects in the ΔAaMip1 were restored in the complementation (CP) strain after re-expressing a functional copy of AaMip1. This study increases our understanding of how A. alternata deals with toxic ROS, triggers autophagy formation, maintains normal cell wall integrity, and regulates toxin metabolism via the AaMip1-mediated signaling pathways.
    DOI:  https://doi.org/10.1094/MPMI-12-24-0161-R
  55. Calcif Tissue Int. 2025 Mar 14. 116(1): 52
    Loss of the Ubiquitin-Associated Domain of sqstm1/p62 in Zebrafish Causes a Phenotype Resembling Paget's Disease of Bone.
    Yentl Huybrechts, Raphaël De Ridder, Dylan Bergen, Björn De Samber, Eveline Boudin, Francesca Tonelli, Dries Knapen, Lucia Vergauwen, Dorien Schepers, Evelien Van Dijck, Qiao Tong, Anja Verhulst, Jan De Beenhouwer, Jan Sijbers, Chrissy Hammond, Antonella Forlino, Geert Mortier, Paul Coucke, P Eckhard Witten, Ronald Young Kwon, Andy Willaert, Gretl Hendrickx, Wim Van Hul.
      The ubiquitin-binding protein p62, encoded by Sequestosome 1 (SQSTM1), is an essential molecular adaptor for selective autophagy. Heterozygous mutations deleting or disrupting the ubiquitin-associated (UBA) domain of p62 have been reported as the major genetic cause for Paget's disease of bone (PDB), the second most common skeletal disease, characterized by hyperactive osteoclasts and focal increases of bone turnover. In this study, we aimed to determine the impact of a similar sqstm1/p62 mutation on the skeleton of zebrafish. We successfully established a sqstm1tmΔUBA zebrafish line with premature truncation of the UBA domain and performed skeletal phenotyping of heterozygous and homozygous mutant zebrafish. Homozygous sqstm1tmΔUBA zebrafish suffered from early lethality after 6 mpf, possibly related to a dysregulated autophagy process. Nevertheless, we detected skeletal abnormalities that were generally more severe in older animals and in homozygous versus heterozygous sqstm1tmΔUBA zebrafish. MicroCT analysis and histologic staining showed alterations in the vertebral bodies and/or bone density in heterozygous sqstm1tmΔUBA zebrafish. We also detected signs of osteocytic osteolysis in carriers of a mutant sqstm1tmΔUBA allele, shown by a higher percentage of enlarged osteocyte lacunae at 12mpf (36% in heterozygote mutants, 20% in wild types). By performing scale histomorphometry, we also detected a higher degree of scale resorption in homozygous sqstm1tmΔUBA zebrafish at 6 mpf. In conclusion, we have generated a Sqstm1 mutant zebrafish model with features of PDB, characterized by focal bone defects and increased osteoclast activity. This model may be useful to further define PDB disease mechanisms and other p62-related (patho)physiological processes.
    Keywords:   sqstm1 ; Genetic animal model; Paget’s disease of bone; UBA; Zebrafish
    DOI:  https://doi.org/10.1007/s00223-025-01360-2
  56. Cell Mol Life Sci. 2025 Mar 13. 82(1): 111
    AMPK activation by hepatitis E virus infection inhibits viral replication through attenuation of autophagosomes and promotion of innate immunity.
    Chunling Wang, Xiaoman Liu, Yao Zhao, Shumin Liao, Jiayue Zhang, Yanhong Huang, Yue Shi, Liang Li, Qiuwei Pan, Jian Wu, Yijin Wang.
      Hepatitis E virus (HEV) infection is generally asymptomatic or leads to acute and self-limiting hepatitis. The mechanisms orchestrating such an infection course remain to be elucidated. AMP-activated protein kinase (AMPK) is a pivotal cellular sensor for maintaining metabolic homeostasis. Here, we show that AMPK is activated in response to HEV infection and is associated with mitochondrial damage and ATP deficiency. AMPK activation, in turn, inhibits HEV replication. Mechanistic studies reveal that AMPK activation triggers the expression of interferon (IFN)-stimulated genes that possess antiviral properties. In parallel, AMPK inhibits autophagosome accumulation to exert antiviral effects. Interestingly, AMPK activation also suppresses the inflammatory response triggered by HEV infection. Consistently, AMPK activation simultaneously exerts anti-inflammatory and antiviral effects in a coculture system of HEV-infected liver cells with macrophages. These findings pave the way for the development of AMPK-targeted therapeutics to treat hepatitis E.
    Keywords:  Antiviral medication; Metabolism; TBK1; Viral infection
    DOI:  https://doi.org/10.1007/s00018-025-05634-8
  57. Cell Mol Life Sci. 2025 Mar 07. 82(1): 105
    IGF2BP1-HAX-1 positive feedback loop-mediated HAX-1 overexpression blocks autophagic flux and promotes chemoresistance in nasopharyngeal carcinoma.
    Siyu Zhang, Miao Gu, Haimeng Yin, Si Pan, Haijing Xie, Wenhui Chen, Sheraz Gul, Yue Zhao, Zhefang Wang, Wenjie Zheng, Yiwen You, Bo You.
      Autophagy is associated with chemoresistance, which is the leading cause of failure in chemotherapeutic treatments. Among the various aspects of autophagy, autophagic flux serves as a critical indicator for evaluating the dynamic processes involved.We report herein that the multifunctional protein HAX-1 promotes chemoresistance by effectively blocking the fusion of autophagosomes with lysosomes. Complementary mass spectrometric and functional studies also demonstrated that HAX-1 recruits NEDD4 to promote Rab7a degradation and inhibits binding of Rab7a with SNAREs by competitively binding to it. Furthermore, HAX-1 binds IGF2BP1 mRNA, thereby contributing to its stability and translation. Moreover, IGF2BP1 enhanced HAX-1 m6A methylation, thereby enhancing its stability. By way of in-vivo and in-vitro experiments, we confirmed the positive role of the IGF2BP1-HAX-1 feedback loop in chemoresistance. Taken together, our findings provide evidence that monitoring of HAX-1, IGF2BP1, and SQSTM1 levels can serve as useful predictors of clinical outcome and chemoresistance risk. In addition, our data provide new insights into the clinical applications of therapies related to autophagic flux and its associated molecular network in targeting cisplatin chemoresistance in nasopharyngeal carcinoma.
    Keywords:  Autophagic flux; Carcinoma; Chemoresistance; HAX-1; IGF2BP1; Nasopharyngeal; Rab7a
    DOI:  https://doi.org/10.1007/s00018-025-05604-0
  58. Eur J Pharmacol. 2025 Mar 08. pii: S0014-2999(25)00235-3. [Epub ahead of print]997 177481
    Mitigating effects of H3 receptor antagonism on cerebellar autophagic pathways and behavioral phenotypes in BTBR T+ tf/J mouse model of autism spectrum disorder.
    Nermin Eissa, Petrilla Jayaprakash, Shouq Aljneibi, Abdallah Alsaadi, Shaikha Alzaabi, Dorota Łazewska, Tadeusz Karcz, Katarzyna Kieć-Kononowicz, Bassem Sadek.
      Accumulation of evidence suggested the involvement of autophagic pathways and their associated AktmTOR (mammalian target of rapamycin) signalling cascade in the pathogenesis of autism spectrum disorder (ASD). Histamine 3 receptors antagonism may be neuroprotective in ASD, as this antagonism modulates autophagy which is reported to be impaired in ASD. Therefore, the effects the novel H3 receptor antagonist E169 (2.5, 5, and 10 mg/kg, i.p.) on short-term memory (STM), long-term memory (LTM), and anxiety level in male Black and Tan BRachyury (BTBR) mice were evaluated using Novel object recognition test (NORT) and open field locomotor (OFT) tests respectively. In NORT, E169 (2.5 mg/kg, i.p.) significantly improved the memory of tested BTBR mice, and the effects of E169 were similar to those of the reference mTOR inhibitor rapamycin, and were reversed following co-administration with the centrally penetrant H3 receptor agonist (R)-α-methylhistamine (RAMH). Furthermore, E169 enhanced the BTBR memory by inhibiting H3 receptors and regulating the extent of disruption in the expression of cerebellar Akt, mTOR, and LC-3 proteins of treated mice. Moreover, E169 (2.5 mg/kg, i.p.) restored the disturbed anxiety levels and hyperactivity observed in OFT. In summary, the findings indicate that H3 receptor antagonists like E169 could play a role in simultaneously regulating disrupted brain neurotransmitters and the dysregulated cerebellar Akt-mTOR signaling pathway associated with autophagy in neurological diseases. Therefore, activation of cerebellar autophagy represented by H3 receptor antagonist E169 may serve as an effective pharmacological therapeutic target for the ASD-like behavioral phenotypes and may add new therapeutic management strategy for the multifactorial disorder ASD.
    Keywords:  ASD; Akt-mTOR; BTBR mice; Cerebellar autophagy; Cognition; Histamine 3 receptor antagonists; Memory
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177481
  59. J Ovarian Res. 2025 Mar 11. 18(1): 49
    Intrinsic differences in mTOR activity mediates lineage-specific responses to cyclophosphamide in mouse and human granulosa cells.
    Shiqian Xu, Yerong Ma, Yinli Zhang, Hanqi Ying, Xiaomei Tong, Weijie Yang, Yibin Pan, Yan Rong, Yangyang Dai, Songying Zhang, Peidong Han.
       BACKGROUND: Cyclophosphamide (CTX) often induces oocyte and granulosa cell injury, leading to fertility loss in young female cancer survivors. Deciphering the mechanisms underlying follicular cell injury could offer novel insights into fertility preservation. Granulosa cells represent the most abundant cell type within the follicles and can be generally categorized as cumulus granulosa cells (CGCs) and mural granulosa cells (MGCs). Despite the essential roles of granulosa cells in supporting ovarian function in physiological conditions, their distinct lineage-specific responses to CTX remains elusive.
    RESULTS: Here, we performed a genome-wide transcriptome analysis of murine mural and cumulus granulosa cells before and after CTX administration. Compared with MGCs, CGCs exhibited higher basal mammalian target of rapamycin (mTOR) activity and an increased DNA damage response post-injury. Pharmacological mTOR suppression or RNA interference-mediated gene silencing of Raptor, a key component of the mTORC1 complex, significantly reduced DNA damage in granulosa cells induced by 4-HC, an activated form of CTX. Notably, by examining human granulosa cells in response to 4-HC, our results uncovered a conserved role of mTOR inhibition in ovarian protection.
    CONCLUSIONS: Taken together, our findings reveal that intrinsic variations in mTOR activity in CGC and MGC lineages determine their differential responses to CTX. Targeting this signaling pathway may prove beneficial in mitigating CTX-induced granulosa cell apoptosis and protecting against ovarian injury.
    Keywords:  Apoptosis; Cyclophosphamide; DNA damage response; Granulosa cells; mTOR signaling pathway
    DOI:  https://doi.org/10.1186/s13048-025-01627-0
  60. Adv Biol (Weinh). 2025 Mar 12. e2400814
    The Aging Substantia Nigra is Characterized by ROS Accumulation Potentially Resulting in Increased Neuroinflammation and Cytoskeletal Remodeling.
    Britta Eggers, Simone Steinbach, Isabel Gil Aldea, Sharon Keers, Mariana Molina, Lea T Grinberg, Helmut Heinsen, Renata E Paraizo Leite, Johannes Attems, Caroline May, Katrin Marcus.
      Aging is a progressive and irreversible process, serving as the primary risk factor for neurodegenerative disorders. This study aims to identify the molecular mechanisms underlying physiological aging within the substantia nigra, which is primarily affected by Parkinson's disease, and to draw potential conclusions on the earliest events leading to neurodegeneration in this specific brain region. The characterization of essential stages in aging progress can enhance knowledge of the mechanisms that promote the development of Parkinson's disease. To gain a comprehensive overview three study groups are utilized: young individuals (mean age: 28.7 years), middle-aged (mean age: 62.3 years), and elderly individuals (mean age: 83.9 years). Using the proteomic approach, crucial features of physiological aging are able to be identified. These include heightened oxidative stress, enhanced lysosomal degradation, autophagy, remodeling of the cytoskeleton, changes in the structure of the mitochondria, alterations in vesicle transportation, and synaptic plasticity.
    Keywords:  aging; data independent acquisition; dopaminergic neurons; laser microdissection; proteomics; substantia nigra
    DOI:  https://doi.org/10.1002/adbi.202400814
  61. Front Cell Dev Biol. 2025 ;13 1465092
    Autophagy: regulating the seesaw of bone-fat balance.
    Boya Zhang, Jing Cui, Xu Zhang, Ziyi Pan, Liuyi Du, RongRong Ye, Linlin Wen, Wenhao Zhai, Lei Huang, Daowei Li, Hongchen Sun.
      The interrelationship between bone and fat can be described as a seesaw in bone homeostasis, in which both osteogenesis and adipogenesis occur in a delicate balance. Osteoblasts and adipocytes share a common origin and play key roles in osteogenesis and adipogenesis. Bone-fat balance indicates osteogenesis and adipogenesis keeps a balance for concordant distribution of trabecular bone and bone marrow adipose tissue in bone, thereby leading to the balance between bone metabolism and lipid metabolism. Bone-fat balance is crucial for metabolic health. When disrupted by various factors, this balance can lead to several bone-related metabolic diseases and systemic disorders, such as obesity, osteoporosis, and osteoarthritis. Recent research highlights the role of autophagy dysfunction in these metabolic conditions. Restoring autophagic function can help restore metabolic homeostasis and re-establish the bone-fat balance. The current review explores the factors that regulate bone-fat balance, the consequences of imbalance under pathological conditions, and the potential of autophagy modulation as a therapeutic approach. Overall, it can be concluded that targeting autophagy presents a promising strategy for treating metabolic disorders and restoring bone-fat balance.
    Keywords:  autophagy; bone diseases; bone metabolism; lipid metabolism; metabolism
    DOI:  https://doi.org/10.3389/fcell.2025.1465092
  62. J Dent Res. 2025 Mar 12. 220345251315723
    Role of Pink1 in Regulating Osteoclast Differentiation during Periodontitis.
    H Gou, T Wang, Y Chen, Y Zhou, J Li, Y Xu.
      Periodontitis has recently been recognized as an inflammatory disease caused by oxidative stress, with mitochondrial dysfunction being a key factor leading to oxidative stress. PTEN-induced kinase 1 (PINK1) is an essential protein for mitochondrial quality control, which protects cells from oxidative stress by inducing mitophagy to degrade damaged mitochondria, but its role in periodontitis has not been elucidated. This study aimed to explore the contribution and underlying mechanisms of Pink1 in regulating the differentiation and function of osteoclasts during periodontitis. Here we observed a significant downregulation of PINK1 expression in periodontitis-affected tissues. Then we constructed a periodontitis model in mice with fluorescently labeled mononuclear/macrophages, and the results showed that as the modeling time extended, the alveolar bone destruction gradually worsened and was accompanied by gradually decreased Pink1 expression in osteoclasts and a significantly increased osteoclast number. In vitro experiments further demonstrated a negative correlation between Pink1 and osteoclast differentiation. In addition, alveolar bone destruction in the Pink1 knockout mice was significantly more advanced than that in the littermate wild type mice after ligature-induced periodontitis and enhanced osteoclastogenesis and bone-resorptive capacity in vitro. RNA-sequencing analysis and in vitro validation revealed that the absence of Pink1 led to a decrease in oxidative phosphorylation levels and an enhancement of calcium-mediated signaling, specifically the calcineurin-NFATc1 pathway, via an intracellular calcium source. Further mechanistic studies found that the deficiency of Pink1 inhibited mitophagy but strengthened mitochondrial-endoplasmic reticulum coupling, which, by promoting the interaction of Mfn2-IP3R-VDAC1 proteins, increased the concentration of mitochondrial calcium ions, thereby triggering more active osteoclast differentiation. The aforementioned process can be reversed by the IP3R channel inhibitor Bcl-XL. These findings unveiled that Pink1 was involved in osteoclast differentiation by regulating mitochondrial calcium transport mediated by mitochondria-associated endoplasmic reticulum membranes, providing a new theoretical basis for the pathogenesis and treatment of periodontitis.
    Keywords:  alveolar bone loss; calcium signaling; mitochondria-associated endoplasmic reticulum membranes; mitophagy; osteoclastogenesis
    DOI:  https://doi.org/10.1177/00220345251315723
  63. Cell Signal. 2025 Mar 05. pii: S0898-6568(25)00130-5. [Epub ahead of print]131 111717
    Mst1 knockout and Nrf2 activation alleviate diabetic cardiomyopathy pathogenesis through autophagy modulation in type 2 diabetic mice.
    Jun Wang, Lulu Wang, Huixiang Zhang, Runbo Tang, Wensi Xu, Nana Meng, Yu Zhao, Yang Liu, Guangwei Li, Yan Lin.
      Diabetic cardiomyopathy (DCM) is a myocardial disorder resulting from glucose metabolism dysfunction, leading to structural and functional heart abnormalities independent of common cardiovascular conditions. This study explores the impact of Mammalian Sterile20-like Kinase 1 (Mst1) and Nuclear Factor E2-Related Factor 2 (Nrf2) pathways on autophagy in type 2 diabetic mice. By employing Mst1 knockout and Nrf2 activation, improvements in cardiac function reduced myocardial fibrosis, and decreased cardiomyocyte apoptosis was observed, with enhanced autophagy noted in Mst1 knockout mice further augmented by Nrf2 activation. The Mst1/Nrf2 pathway demonstrates a protective effect by regulating autophagy-related proteins, offering a potential therapeutic avenue for treating DCM in type 2 diabetes.
    Keywords:  Autophagy; Cardiac function; Diabetic cardiomyopathy; Mammalian Sterile20-like kinase 1; Myocardial fibrosis; Nuclear factor E2-related factor 2
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111717
  64. Apoptosis. 2025 Mar 10.
    Melatonin attenuates inflammatory bone loss by alleviating mitophagy and lactate production.
    Zexin Lin, Yuan Gu, Yingsong Liu, Zilin Chen, Shuai Fang, Zhuan Wang, Zixian Liu, Qingrong Lin, Yanjun Hu, Nan Jiang, Bin Yu, Guanqiao Liu.
      Mitochondrial homeostasis plays a major role in the progression of chronic inflammatory bone loss which has a complex pathogenesis with unsatisfactory therapeutic efficiency. Recently, melatonin has been shown to recipient mitochondrial function and bone formation. However, the effects and underlying molecular mechanism of melatonin in chronic inflammatory bone loss remain unclear. Here, we reported that melatonin ameliorated lipopolysaccharide (LPS)-induced inflammatory bone loss by improving osteogenesis. We found that melatonin rescued LPS-induced mitochondrial dysfunction and metabolic reprogramming in osteoblasts, resulting in reduced osteogenesis impairment. Mechanistically, melatonin inhibited mitochondrial reactive oxygen species (mtROS) production by suppressing LPS-induced mitophagy, which attenuated the activation of the mtROS/HIF-1α/pyruvate dehydrogenase kinase 1 (PDK1) axis. Moreover, melatonin restored pyruvate dehydrogenase (PDH) activity by inhibiting phosphorylation of PDH through the mtROS/HIF-1α/PDK1 axis and eventually downregulated lactate production. These findings indicate the therapeutic effects of melatonin against chronic inflammatory bone loss and demonstrated a potential treatment strategy against inflammatory osteogenic disorders through regulating mitochondrial dysfunction and metabolic reprogramming.
    Keywords:  Inflammatiory bone loss; Lactate; Melatonin; Mitochondrial reactive oxygen species; Mitophagy
    DOI:  https://doi.org/10.1007/s10495-025-02096-y
  65. Proc Natl Acad Sci U S A. 2025 Mar 11. 122(10): e2402117122
    Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.
    Elizabeth A Johnson, Raghad Nowar, Kirsten L Viola, Weijian Huang, Sihang Zhou, Maíra A Bicca, Wei Zhu, Daniel L Kranz, William L Klein, Richard B Silverman.
      Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., Clin. Transl. Med. 11, e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (AβOs), small peptide aggregates that are instigators of Alzheimer's disease neurodegeneration [M. Tolar et al., Int. J. Mol. Sci. 22, 6355 (2021)]. AβO buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L- and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against AβO buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.
    Keywords:  Alzheimer’s disease; amyloid-beta oligomers; neurodegenerative disease; protein aggregation
    DOI:  https://doi.org/10.1073/pnas.2402117122
  66. Exp Eye Res. 2025 Mar 08. pii: S0014-4835(25)00099-5. [Epub ahead of print] 110328
    SIRT3 mitigates dry eye disease through the activation of autophagy by deacetylation of FOXO1.
    Di Zhang, Qi Liang, Jiaxuan Jiang, Wei Liu, Yiran Chu, Zeying Chen, Boda Li, Taige Chen, Jia-Ruei Tsao, Kai Hu.
      Dry eye disease (DED) is a complex ocular condition characterized by oxidative stress, inflammation, and apoptosis. An increasing number of studies suggest that Sirtuin3 (SIRT3), a mitochondrial deacetylase, may offer protection against related pathologies. Despite these indications, the precise function and underlying mechanisms of SIRT3 in the context of DED have not been fully elucidated. Here, we observed a decline in SIRT3 expression in human corneal epithelial cells (HCE-Ts) and the corneal conjunctiva of mice as the disease advanced. Overexpression of SIRT3 in HCE-Ts reduced the accumulation of reactive oxygen species (ROS), inflammatory cytokines, and the rate of apoptosis, while its inhibition had the opposite effect. Importantly, the function of SIRT3 was exerted through the enhancement of autophagic flux. Further studies have shown that chloroquine-induced inhibition of autophagy neutralized the beneficial effects of SIRT3. In our in vivo experiments, the application of eye drops containing a SIRT3 agonist ameliorated the symptoms of DED and increased corneal autophagy in mice. Mechanistically, our study identified that the deacetylation and nuclear translocation of FOXO1 (Forkhead box O1) are pivotal for the SIRT3-mediated enhancement of autophagic flux. These findings posit that SIRT3 as an encouraging therapeutic target for DED, offering new insights into the disease's underlying mechanisms.
    Keywords:  Autophagy; FOXO1; SIRT3; deacetylation; dry eye disease
    DOI:  https://doi.org/10.1016/j.exer.2025.110328
  67. Nat Commun. 2025 Mar 13. 16(1): 2504
    Selective regulation of corticostriatal synapses by astrocytic phagocytosis.
    Ji-Young Kim, Hyeyeon Kim, Won-Suk Chung, Hyungju Park.
      In the adult brain, neural circuit homeostasis depends on the constant turnover of synapses via astrocytic phagocytosis mechanisms. However, it remains unclear whether this process occurs in a circuit-specific manner. Here, we reveal that astrocytes target and eliminate specific type of excitatory synapses in the striatum. Using model mice lacking astrocytic phagocytosis receptors in the dorsal striatum, we found that astrocytes constantly remove corticostriatal synapses rather than thalamostriatal synapses. This preferential elimination suggests that astrocytes play a selective role in modulating corticostriatal plasticity and functions via phagocytosis mechanisms. Supporting this notion, corticostriatal long-term potentiation and the early phase of motor skill learning are dependent on astrocytic phagocytic receptors. Together, our findings demonstrate that astrocytes contribute to the connectivity and plasticity of the striatal circuit by preferentially engulfing a specific subset of excitatory synapses within brain regions innervated by multiple excitatory sources.
    DOI:  https://doi.org/10.1038/s41467-025-57577-0
  68. bioRxiv. 2025 Feb 27. pii: 2025.02.26.640437. [Epub ahead of print]
    Structural basis for anomalous cellular trafficking behavior of glaucoma-associated A427T mutant myocilin.
    Kamisha R Hill, Hailee F Scelsi, Hannah A Youngblood, Jennifer A Faralli, Tatsuo Itakura, M Elizabeth Fini, Donna M Peters, Raquel L Lieberman.
      Familial mutations in myocilin cause vision loss in glaucoma due to misfolding and a toxic gain of function in a senescent cell type in the anterior eye. Here we characterize the cellular behavior and structure of the myocilin (myocilin A427T) mutant, of uncertain pathogenicity. Our characterization of A427T demonstrates that even mutations that minimally perturb myocilin structure and stability can present challenges for protein quality control clearance pathways. Namely, when expressed in an inducible immortalized trabecular meshwork cell line, inhibition of the proteasome reroutes wild-type myocilin, but not myocilin A427T, from endoplasmic reticulum associated degradation to lysosomal degradation. Yet, the crystal structure of the A427T myocilin olfactomedin domain shows modest perturbations largely confined to the mutation site. The previously unappreciated range of mutant myocilin behavior correlating with variable stability and structure provides a rationale for why it is challenging to predict causal pathogenicity of a given myocilin mutation, even in the presence of clinical data for members of an affected family. Comprehending the continuum of mutant myocilin behavior in the laboratory supports emerging efforts to use genetics to assess glaucoma risk in the clinic. In addition, the study supports a therapeutic strategy aimed at enhancing autophagic clearance of mutant myocilin.
    DOI:  https://doi.org/10.1101/2025.02.26.640437
  69. Science. 2025 Mar 13. eadu6445
    Structure of human PINK1 at a mitochondrial TOM-VDAC array.
    Sylvie Callegari, Nicholas S Kirk, Zhong Yan Gan, Toby Dite, Simon A Cobbold, Andrew Leis, Laura F Dagley, Alisa Glukhova, David Komander.
      Mutations in the ubiquitin kinase PINK1 cause early onset Parkinson's Disease, but how PINK1 is stabilized at depolarized mitochondrial translocase complexes has remained poorly understood. We determined a 3.1-Å resolution cryo-electron microscopy structure of dimeric human PINK1 stabilized at an endogenous array of mitochondrial TOM and VDAC complexes. Symmetric arrangement of two TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and TOM20, both of which also bind PINK1 kinase C-lobes. PINK1 enters mitochondria through the proximal TOM40 barrel of the TOM core complex, guided by TOM7 and TOM22. Our structure explains how human PINK1 is stabilized at the TOM complex and regulated by oxidation, uncovers a previously unknown TOM-VDAC assembly, and reveals how a physiological substrate traverses TOM40 during translocation.
    DOI:  https://doi.org/10.1126/science.adu6445
  70. Am J Chin Med. 2025 Mar 12. 1-25
    Chinese Medicine for the Treatment of Liver Cirrhosis: The Mechanism of Cellular Autophagy.
    Shihao Zheng, Tianyu Xue, Qiuyue Wang, Pingxin Zhang, Wenying Qi, Chengyuan Xue, Xiaoke Li, Hongbo Du, Peng Zhang, Xiaobin Zao, Yongan Ye.
      Liver cirrhosis is a critical stage in the progression of various chronic liver diseases, often leading to severe complications such as ascites, hepatic encephalopathy, and a high mortality rate, and it thus poses a serious threat to patient life. The activation of hepatic stellate cells is a central driver of disease progression. Cellular autophagy, a lysosome-mediated degradation process, plays a key role in maintaining cellular function and dynamic homeostasis. Research has shown that autophagy is closely associated with proteins like LC3, Beclin-1, P62, and mTOR, and is regulated through signaling pathways such as PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, and AMPK/mTOR. Additionally, the relationship between autophagy and apoptosis, as well as between autophagy and exosomes, has been further demonstrated. While modern medicine has made progress in treating cirrhosis, it still faces significant limitations. By contrast, numerous studies have demonstrated the efficacy of traditional Chinese medicine in preventing and treating liver cirrhosis by regulating autophagy, with fewer adverse effects. Chinese herbal monomers and formulations can modulate various autophagy-related signaling pathways, including PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, and AMPK/mTOR, and influence key autophagy proteins such as LC3 and Beclin-1. This modulation inhibits hepatic stellate cell activation, reduces extracellular matrix deposition, and exerts anticirrhotic effects. Moreover, Chinese medicine appears to reduce adverse reactions in cirrhosis treatment and lower the risk of disease recurrence. This review explores the mechanisms of autophagy in the prevention and treatment of liver cirrhosis through Chinese medicine, offering new insights for the development of Chinese medicinal therapies for cirrhosis and their rational clinical application.
    Keywords:  Cellular Autophagy; Chinese Medicine; Liver Cirrhosis; Mechanism; Signaling Pathway
    DOI:  https://doi.org/10.1142/S0192415X25500168
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