bims-auttor 2025-06-01 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–06–01
39 papers selected by
Viktor Korolchuk, Newcastle University

The pathway of autophagy in the epigenetic landscape of Mycobacterium-host interactions.
Endoplasmic reticulum tubule junctions are sites of autophagy.
Review of FUNDC1-mediated mitochondrial autophagy in Alzheimer's disease.
Phagophore Ceramide Promotes LC3 Lipidation and Autophagy in T-Lymphoid Cell Death.
Defective autophagy in a fibroin secretion-deficient silkworm mutant.
Autophagy in cardiac pathophysiology: Navigating the complex roles and therapeutic potential in cardiac fibrosis.
Evidence of an unprecedented cytoplasmic function of DDX11, the Warsaw breakage syndrome DNA helicase, in regulating autophagy.
Improved detection of lipidated Atg8a by immunoblotting in drosophila melanogaster cells and tissues enables precise investigation of Atg8a flux and its termination.
MCOLN1/TRPML1-MCOLN3/TRPML3 heteromer and its coupling to Ca2+ sensor SYT5 regulates autophagosome-lysosome fusion in a PtdIns4P-dependent manner.
The AKT-USP15 axis modulates autophagy in MPP+-induced Parkinson's disease model of SN4741 cells.
Structural insights into autophagy in the AlphaFold era.
Can autophagy enhance crop resilience to environmental stress?
mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node.
The dual role of autophagy in cancer stem cells: implications for tumor progression and therapy resistance.
c-Abl/TFEB Pathway Activation as a Common Pathogenic Mechanism in Lysosomal Storage Diseases: Therapeutic Potential of c-Abl Inhibitors.
Research progress on the autophagy gene ATG6 in planta.
KEAP1 retention in phase-separated p62 bodies drives liver damage under autophagy-deficient conditions.
YTHDF1 differentiates the contributing roles of mTORC1 in aging.
Recovery of Lysosomal Acidification and Autophagy Flux by Attapulgite Nanorods: Therapeutic Potential for Lysosomal Disorders.
CO confers neuroprotection via activating the PERK-calcineurin pathway and inhibiting necroptosis.
Macroautophagy at the service of synapses.
Extracellular Vesicles in the Crosstalk of Autophagy and Apoptosis: A Role for Lipid Rafts.
Dysregulation of autophagy during photoaging reduce oxidative stress and inflammatory damage caused by UV.
Advances in Targeted Autophagy Modulation Strategies to Treat Cancer and Associated Treatment-Induced Cardiotoxicity.
UPS10 inhibits the degradation of α-synuclein, a pathogenic factor associated with Parkinson's disease, by inhibiting chaperone-mediated autophagy.
Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.
Autophagy promotes the acquisition of genotoxic resistance in cancer cells in a paracrine manner via upregulation of PLK1-RAD9A axis.
The Role of Intermittent Fasting in the Activation of Autophagy Processes in the Context of Cancer Diseases.
Loss of hepatic autophagy induces α-cell proliferation through impaired glutamine-dependent gluconeogenesis.
WNK1 signalling regulates amino acid transport and mTORC1 activity to sustain acute myeloid leukaemia growth.
mTOR signaling regulates the development of airway mucous cell metaplasia associated with severe asthma.
A Novel Function of NaV Channel β3 Subunit in Endothelial Cell Alignment Through Autophagy Modulation.
NAP1L1 degradation by FBXW7 reduces the deubiquitination of HDGF-p62 signaling to stimulate autophagy and induce primary cisplatin chemosensitivity in nasopharyngeal carcinoma.
Misregulation of the Ubiquitin-Proteasome System and Autophagy in Muscular Dystrophies Associated with the Dystrophin-Glycoprotein Complex.
Targeting Methionine Metabolism Reveals AMPK-SAMTOR Signaling as a Therapeutic Vulnerability in Prostate Cancer.
The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan.
Research on the role and mechanism of the PI3K/Akt/mTOR signalling pathway in osteoporosis.
Evaluation of aggrephagy markers in myofibrillar myopathies.
Unveiling EXOC4/SEC8: a key player in enhancing antiviral immunity by inhibiting the FBXL19-STING1-SQSTM1 signaling axis.

Autophagy. 2025 May 31. 1-19

The pathway of autophagy in the epigenetic landscape of Mycobacterium-host interactions.

Abhishek Mishra, Varsha Rawat, Kangling Zhang, Chinnaswamy Jagannath.

  Macroautophagy (autophagy) is an evolutionarily conserved process that degrades excess cytoplasmic components, such as protein aggregates and damaged organelles, by encapsulating them within double-membrane autophagosomes. These autophagosomes undergo distinct stages - initiation, phagophore nucleation, expansion, and closure - before fusing with lysosomes (or occasionally endosomes) for degradation and recycling. This process is regulated by ATG (autophagy related) proteins, which govern autophagosome formation and lysosomal fusion. Epigenetic modifications and transcription factors can regulate ATG gene expression in the nucleus. Autophagy also plays a key role in eliminating intracellular Mycobacterium tuberculosis (Mtb) through the lytic and antimicrobial activities of autolysosomes, which are more potent antimicrobial compartments than conventional phagosomes. Emerging evidence suggests that Mtb can modify the host epigenome and transcriptional machinery, significantly affecting the host immune response. This review explores the epigenetic regulation of autophagy during mycobacterium-host interactions. The interplay between epigenetic regulation and autophagy highlights a crucial aspect of host-pathogen interactions during Mtb infection. Understanding how Mtb manipulates the host epigenome to regulate autophagy could lead to the development of novel therapeutic strategies that enhance autophagic pathways or counteract Mtb's immune evasion tactics.Abbreviations: AM: Alveolar macrophages; ATG: autophagy related; DNMT: DNA methyltransferase; FOXO3: forkhead box O3; HAT: histone acetyltransferase; HDAC: histone deacetylase; MIR: microRNA; MTOR: mechanistic target of rapamycin kinase; Mtb: Mycobacterium tuberculosis; ROS: reactive oxygen species; SIRT: sirtuin; STPK: serine/threonine protein kinase.

Keywords:  Autophagy; epigenetics; histone modification; host-pathogen interactions; microRNA; tuberculosis

DOI:  https://doi.org/10.1080/15548627.2025.2511074
Autophagy. 2025 May 25.

Endoplasmic reticulum tubule junctions are sites of autophagy.

Susan Ferro-Novick.

  Selective endoplasmic reticulum (ER) macroautophagy/autophagy, also called reticulophagy, is a disposal pathway that degrades ER domains. A major role of reticulophagy is the removal of ER domains that contain misfolded proteins resistant to ER-associated degradation (ERAD). Our studies have shown that RTN3L, the SEC24C-SEC23 COPII coat subcomplex, and the CUL3KLHL12 E3 ligase that ubiquitinates RTN3L targets ERAD-resistant misfolded protein condensates for degradation at ER-reticulophagy sites (ERPHS), autophagic sites that form at tubule junctions. Unexpectedly, we found that the Parkinson disease protein PINK1 regulates ER tubulation. Loss of PINK1 disrupts the formation of peripheral tubule junctions, and, as a consequence, reticulophagy is blocked and misfolded proteins accumulate in the ER. Overexpression of the ER tubulating domain of DNM1L/DRP1, a multifunctional PINK1 kinase substrate that localizes to ER-mitochondria contact sites, increases junctions and restores reticulophagy. Our findings show that PINK1 shapes the ER to target misfolded proteins for RTN3L-SEC24C-mediated macroreticulophagy at defined ER sites, peripheral tubule junctions.

Keywords:  ER junctions; ER quality control; Reticulophagy

DOI:  https://doi.org/10.1080/15548627.2025.2508934
Front Aging Neurosci. 2025 ;17 1544241

Review of FUNDC1-mediated mitochondrial autophagy in Alzheimer's disease.

Dandan Shi, Xiaochen Guo, Ziqi Ning, Yaoyao Zhang, Fang Liu, Meixia Liu, Yun Wei.

  Mitochondrial autophagy is a critical quality control mechanism that eliminates dysfunctional mitochondria to maintain cellular homeostasis. Among receptor-dependent mitophagy pathways, FUN14 domain-containing 1 (FUNDC1)-a mitochondrial outer membrane protein harboring an LC3-interacting region (LIR)-plays a central role by directly binding to LC3 under stress conditions, thereby initiating autophagosome encapsulation of damaged organelles. Emerging evidence implicates FUNDC1 dysregulation in neurodegenerative diseases, particularly Alzheimer's disease (AD), where defective mitophagy exacerbates hallmark pathologies including Aβ plaque deposition and hyperphosphorylated Tau-driven neurofibrillary tangles. Despite advances, the molecular interplay between FUNDC1 phosphorylation states (e.g., Ser13/Ser17/Tyr18) and AD progression remains poorly defined. This review systematically examines FUNDC1's dual regulatory role in mitophagy, its mechanistic links to Aβ and Tau pathologies, and the therapeutic potential of targeting FUNDC1-associated kinases (e.g., ULK1, CK2) or downstream effectors (e.g., DRP1, OPA1) to counteract mitochondrial dysfunction in AD. By synthesizing recent preclinical and clinical findings, we aim to bridge the gap between FUNDC1 biology and AD therapeutics, highlighting actionable nodes for drug development.

Keywords:  Alzheimer’s disease; FUNDC1 signaling pathway; mitochondrial autophagy; neurodegenerative diseases; signaling molecules

DOI:  https://doi.org/10.3389/fnagi.2025.1544241
FASEB J. 2025 Jun 15. 39(11): e70668

Phagophore Ceramide Promotes LC3 Lipidation and Autophagy in T-Lymphoid Cell Death.

Makoto Taniguchi, Shingo Nagaya, Hiromi Kirisako, Yoshinori Ohsumi, Hitoshi Nakatogawa, Toshiro Okazaki.

  The bioactive sphingolipid ceramide induces various types of cell death, including autophagy-dependent cell death (ADCD). However, its role in autophagy and ADCD is not fully understood. Here, we demonstrated that amino acid deprivation (AA[-]) in murine lymphoid WR19L cells promoted the accumulation of ceramide at phagophores and autophagy, resulting in ADCD. Control of ceramide production by sphingomyelin synthase 1 and neutral sphingomyelinase 2 altered cell fate by regulating AA(-)-induced autophagy and ADCD. In vitro reconstruction analysis of phosphatidylethanolamine (PE) binding to microtubule-associated protein-1 light chain-3 (LC3), a key step in phagophore formation leading to autophagic flux, revealed that ceramide promoted the PE lipidation of LC3. These results suggest that ceramide promotes autophagosome formation by enhancing PE lipidation of LC3, leading to excess autophagy and ADCD. This study highlights novel insights into the ceramide/sphingomyelin balance at autophagy-related membranes, which controls the switch on autophagy and ADCD through enhanced lipidation of LC3.

Keywords:  autophagy; autophagy‐dependent cell death; ceramide; sphingomyelin; sphingomyelin synthase; sphingomyelinase

DOI:  https://doi.org/10.1096/fj.202500348R
Autophagy. 2025 May 30. 1-13

Defective autophagy in a fibroin secretion-deficient silkworm mutant.

Jianhua Xia, Haiqin Chen, Yuying Wang, Wenbo Hu, Kaiyu Guo, Qingqing Linghu, Pengchao Guo, Xin Wang, Qingyou Xia, Ioannis P Nezis, Ping Zhao, Zhaoming Dong, Yan Zhang.

  The silkworm Bombyx mori is an economically important insect for silk production. Its silk glands are responsible for the synthesis and secretion of silk proteins. The naked pupa (Nd), a fibroin heavy chain mutant strain of silkworm, was found to exhibit severe atrophy, degeneration of the posterior silk gland (PSG), and abnormal secretion of fibroin proteins, thereby producing little or no silk. Here, we found that the autophagic marker Atg8-PE was upregulated through the target of rapamycin complex 1 signaling pathway in Nd. However, as autophagy substrates, SQSTM1/p62 and ubiquitinated protein levels increased in Nd. Furthermore, treatment with BafA1 showed no effect on the protein levels of SQSTM1/p62, indicating impaired autophagic flux in Nd. Abnormal acidification of lysosomes was further detected, which resulted in a decreased proportion of matured CtsL1 (cathepsin L1). Thus, the substrate in autolysosomes cannot be degraded within a rapid time frame, resulting in the accumulation of protein aggregates, which cause atrophy and degeneration of the PSG. We also found that acidic nanoparticles rescued lysosomal acidification and relieved the degenerative changes of Nd-PSG. The findings of this study suggest that the Nd mutant silkworm can be used as an animal model for studying protein aggregation diseases.Abbreviations: AD: Alzheimer disease; aNP: acidic nanoparticle; APP: amyloid beta precursor protein; Atg8: autophagy related 8; BACE1: beta-secretase 1; BafA1: bafilomycin A1; CtsL1: cathepsin L1; CRY: crystallin; ER: endoplasmic reticulum; FibH: fibroin heavy chain; FibL: fibroin light chain; FUS: FUS RNA binding protein; HD: Huntington disease; HRP: horseradish peroxidase; Nd: naked pupa; OSBPL2: oxysterol binding protein like 2; PD: Parkinson disease; PE: phosphatidylethanolamine; p-EIF4EBP: phosphorylated eukaryotic initiation factor 4E binding protein; PROM1: prominin 1; p-RPS6KB: phosphorylated ribosomal protein S6 kinase B; PSEN: presenilin; PSG: posterior silk gland; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SEM: standard error of the mean; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; TARDBP: TAR DNA binding protein; TORC1: target of rapamycin complex 1; UBQLN2: ubiquilin 2; V-ATPase: vacuolar-type ATPase.

Keywords:  Autophagy; Bombyx mori; FibH mutation; Nd mutant; lysosome acidification; posterior silk gland

DOI:  https://doi.org/10.1080/15548627.2025.2510843
Life Sci. 2025 May 24. pii: S0024-3205(25)00396-0. [Epub ahead of print] 123761

Autophagy in cardiac pathophysiology: Navigating the complex roles and therapeutic potential in cardiac fibrosis.

Ling-Xuan Dan, Song-Ping Xie.

  Cardiac fibrosis is a critical factor in cardiac structural remodeling and dysfunction, closely associated with the progression of various cardiovascular diseases (CVDs), including heart failure and myocardial infarction (MI). It is characterized by excessive extracellular matrix (ECM) deposition, which disrupts normal cardiac architecture and impairs cardiac function. Autophagy, a cellular degradation and recycling mechanism, is essential for maintaining cardiac homeostasis, mitigating stress responses, and preventing cellular damage. Recent studies have revealed a significant link between autophagy and cardiac fibrosis, suggesting that autophagic dysregulation can exacerbate fibrosis by promoting fibroblast activation and ECM accumulation. Conversely, proper autophagic activity may attenuate cardiac fibrosis by removing damaged cellular components and regulating fibrotic signaling pathways. This review examines the role of autophagy in cardiac fibrosis. It also emphasizes potential pharmacological strategies that can be used to modulate autophagic processes. These strategies may serve as therapeutic approaches for treating cardiac fibrosis, with the ultimate goal of preventing excessive fibrosis and enhancing cardiac function.

Keywords:  Autophagy; Cardiac fibrosis; Cardiac pathophysiology; Heart failure

DOI:  https://doi.org/10.1016/j.lfs.2025.123761
Autophagy. 2025 May 25.

Evidence of an unprecedented cytoplasmic function of DDX11, the Warsaw breakage syndrome DNA helicase, in regulating autophagy.

Raffaella Bonavita, Antonello Prodomo, Giuseppe Cortone, Fulvia Vitale, Marcello Germoglio, Angeleen Fleming, Jesper A Balk, Job De Lange, Maurizio Renna, Francesca M Pisani.

  DDX11 is a DNA helicase involved in critical cellular functions, including DNA replication/repair/recombination as well as sister chromatid cohesion establishment. Bi-allelic mutations of DDX11 lead to Warsaw breakage syndrome (WABS), a rare genome instability disorder marked by significant prenatal and postnatal growth restriction, microcephaly, intellectual disability, and sensorineural hearing loss. The molecular mechanisms underlying WABS remain largely unclear. In this study, we uncover a novel role of DDX11 in regulating the macroautophagic/autophagic pathway. Specifically, we demonstrate that knockout of DDX11 in RPE-1 cells hinders the progression of autophagy. DDX11 depletion significantly reduces the conversion of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3), suggesting a defect in autophagosome biogenesis. This is supported by imaging analysis with a LC3 reporter fused in tandem with the red and green fluorescent proteins (mRFP-GFP-LC3), which reveals fewer autophagosomes and autolysosomes in DDX11-knockout cells. Moreover, the defect in autophagosome biogenesis, observed in DDX11-depleted cells, is linked to an upstream impairment of the ATG16L1-precursor trafficking and maturation, a step critical to achieve the LC3 lipidation. Consistent with this, DDX11-lacking cells exhibit a diminished capacity to clear aggregates of a mutant HTT (huntingtin) N-terminal fragment fused to the green fluorescent protein (HTTQ74-GFP), an autophagy substrate. Finally, we demonstrate the occurrence of a functional interplay between DDX11 and SQSTM1, an autophagy cargo receptor protein, in supporting LC3 modification during autophagosome biogenesis. Our findings highlight a novel unprecedented function of DDX11 in the autophagy process with important implications for our understanding of WABS etiology.

Keywords:  Autophagosome biogenesis; DDX11; DNA helicase; LC3; SQSTM1/p62; Warsaw breakage syndrome; neurodevelopmental disorders

DOI:  https://doi.org/10.1080/15548627.2025.2507617
Autophagy. 2025 May 27.

Improved detection of lipidated Atg8a by immunoblotting in drosophila melanogaster cells and tissues enables precise investigation of Atg8a flux and its termination.

Siri Andresen, Amani Al Outa, Miriam Formica, Jorrit Enserink, Helene Knævelsrud.

  Macroautophagy/autophagy is an essential intracellular catabolic process for maintaining cellular homeostasis. In Drosophila melanogaster, Atg8a lipidation serves as a key marker for autophagy, yet traditional methods often fail to effectively detect its lipidated state. To overcome this limitation, we developed a refined approach that employs N-ethylmaleimide (NEM) to inhibit Atg4, thereby preserving Atg8a lipidation during sample preparation both in vitro and in vivo. We determined the optimal concentration of the autophagic inhibitors bafilomycin A1 (BafA1) and chloroquine (CQ) required for inhibition of autolysosomal degradation. Furthermore, we investigated the effects of prolonged nutrient deprivation on autophagic flux and TORC1 signaling. Our findings not only validate the effectiveness of this new approach to monitor lipidation of Atg8a but also provide insights into selection of autolysosomal inhibitors and nutrient-dependent regulatory roles of TORC1 in Drosophila.

Keywords:  Atg4; Atg8a; Drosophila; N-ethylmaleimide (NEM); autophagic flux; macroautophagy

DOI:  https://doi.org/10.1080/15548627.2025.2508551
Autophagy. 2025 May 27. 1-17

MCOLN1/TRPML1-MCOLN3/TRPML3 heteromer and its coupling to Ca2+ sensor SYT5 regulates autophagosome-lysosome fusion in a PtdIns4P-dependent manner.

Jin Kwon, So Woon Kim, Seokwoo Hong, Areum Choi, Suzi Choi, Myoung Kyu Park, Hyun Jin Kim.

  Macroautophagy/autophagy progresses through Ca2+-dependent multiple fusion events. Recently, we reported that the intracellular Ca2+ channel MCOLN3/TRPML3 provides Ca2+ for membrane fusion during autophagosome formation as a downstream effector of phosphatidylinositol-3-phosphate (PtdIns3P). However, the molecular mechanism of Ca2+ signaling in the late stage of autophagy remains unknown. Here, we show that the MCOLN1/TRPML1-MCOLN3/TRPML3 heteromer is the Ca2+ provider for autophagosome-lysosome fusion. MCOLN1-MCOLN3 functions downstream of PtdIns4P to release Ca2+ from autophagosomes, and the Ca2+ signal via PtdIns4P-MCOLN1-MCOLN3 is decoded by the Ca2+ sensor SYT5 (synaptotagmin 5). The binding of Ca2+ and PtdIns4P to SYT5 is critical for autophagosome-lysosome fusion by forming a fusion complex. Collectively, these results reveal that PtdIns4P-MCOLN1-MCOLN3-SYT5 constitutes the Ca2+ signaling complex in autophagosome-lysosome fusion and that MCOLN3 also regulates the late stage of autophagy through heteromerization with MCOLN1 in a phosphoinositide (PI)-dependent manner.Abbreviations: ATG, autophagy related; CPA, cyclopiazonic acid; DN, dominant-negative; GPN, glycyl-L-phenylalanine-beta-naphthylamide; KO, knockout; NH4Cl, ammonium chloride; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; PI, phosphoinositide; SYT5, synaptotagmin 5; tfLC3, mRFP-GFP tandem fluorescent-tagged LC3; WT, wild-type.

Keywords:  Autophagy; Ca2+ channel; PI4P; SYT5; TRPML1/3

DOI:  https://doi.org/10.1080/15548627.2025.2510846
Cell Signal. 2025 May 27. pii: S0898-6568(25)00294-3. [Epub ahead of print] 111879

The AKT-USP15 axis modulates autophagy in MPP+-induced Parkinson's disease model of SN4741 cells.

Xian Wu, Yue Wen, Tianyao Bai, Nanfei Yang, Yuyu Yuan, Lingling Xu, Yujie Ma, Peng Su, Wenjing Luo, Wenjun Li.

  In Parkinson's disease (PD), maintaining the balance between protein synthesis and degradation is critical for cellular homeostasis. Ubiquitination, which marks proteins for degradation, and its reverse process deubiquitination, are essential regulators for protein turnover. Recent research implicate that deubiquitinating enzymes involve in PD pathogenesis. Specially, Ubiquitin Specific Protease 15 (USP15) has been shown to antagonize Parkin, an E3 ubiquitin ligase that facilitates mitophagy - the selective clearance of damaged mitochondria.. However, the regulatory mechanisms governing the activity of USP15 in PD remain unclear. Our study revealed a novel regulatory mechanism: USP15 served as a phosphorylation substrate for protein kinase B (AKT). AKT-mediated phosphorylation triggered translocation of USP15 from the nucleus to the cytoplasm, subsequently restoring autophagy levels. These data identified that AKT mediated phosphorylation of USP15 regulated autophagy in MPP+-induced PD models. Collectivelly, our research elucidates the complex interplay among AKT, USP15, and autophagy in PD. These mechanistic insights advance our understanding of potential therapeutic targets to enhance autophagic flux and ameliorate cellular dysfunction in Parkinson's disease.

Keywords:  AKT; Autophagy; Parkinson's disease; Phosphorylation; USP15

DOI:  https://doi.org/10.1016/j.cellsig.2025.111879
J Mol Biol. 2025 May 27. pii: S0022-2836(25)00301-8. [Epub ahead of print] 169235

Structural insights into autophagy in the AlphaFold era.

Tatsuro Maruyama, Nobuo N Noda.

  Autophagy, a lysosomal intracellular degradation system, is characterized by the de novo biogenesis of autophagosomes. This biogenesis is mediated by approximately 20 core Atg proteins, exhibiting a high degree of conservation from yeast to humans. Over the preceding two decades, the structural biology of autophagy has been investigated predominantly through X-ray crystallography, NMR spectroscopy, and, more recently, cryo-electron microscopy, collectively contributing to the elucidation of the structural basis of core Atg proteins. The recent introduction of AlphaFold has significantly improved the precision of structure prediction and is transforming structural biology research. In this review, we aim to synthesize the structural basis of the operational mechanisms of the core Atg proteins, employing structures predicted by AlphaFold, and to discuss the molecular mechanisms that drive autophagosome biogenesis.

Keywords:  AlphaFold; AlphaFold2; AlphaFold3; autophagosome formation; autophagy

DOI:  https://doi.org/10.1016/j.jmb.2025.169235
Philos Trans R Soc Lond B Biol Sci. 2025 May 29. 380(1927): 20240245

Can autophagy enhance crop resilience to environmental stress?

William Agbemafle, Vishadinie Jayasinghe, Diane C Bassham.

  Climate change imposes abiotic stress on plants, significantly threatening global agriculture and food security. This indicates a need to apply our understanding of plant stress responses to improve crop resilience to these threats. Stress damages critical cellular components such as mitochondria, chloroplasts and the endoplasmic reticulum. Left unmitigated, abiotic stress can lead to cell death, which typically decreases overall plant health and productivity. Autophagy is a catabolic process that maintains cellular homeostasis by degrading and recycling damaged and dysfunctional cell components and organelles. Importantly, autophagy promotes plant tolerance to a wide range of environmental stresses, and manipulation of autophagy may lead to improved stress resilience in crops. Here, we discuss recent advances in our understanding of how autophagy affects abiotic stress resistance. We discuss the function of autophagy in different abiotic stresses (including nutrient stress, salt stress, drought, heat, cold, hypoxia, light stress and combined stresses) and provide insights from functional and genome-wide transcriptomic studies. We also evaluate the potential to enhance crop survival and productivity in suboptimal environmental conditions by activating autophagy, emphasizing the importance of targeted manipulation of key genes involved in the autophagy pathway.This article is part of the theme issue 'Crops under stress: can we mitigate the impacts of climate change on agriculture and launch the 'Resilience Revolution'?'.

Keywords:  autophagy; autophagy manipulation; crop improvement; stress response

DOI:  https://doi.org/10.1098/rstb.2024.0245
Orphanet J Rare Dis. 2025 May 27. 20(1): 256

mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node.

Laura Mantoan Ritter, Nicholas M P Annear, Emma L Baple, Leila Y Ben-Chaabane, Istvan Bodi, Lauren Brosson, Jill E Cadwgan, Bryn Coslett, Andrew H Crosby, D Mark Davies, Nicola Daykin, Stefanie Dedeurwaerdere, Christina Dühring Fenger, Elaine A Dunlop, Frances V Elmslie, Marie Girodengo, Sophie Hambleton, Anna C Jansen, Simon R Johnson, Kelly C Kearley, John C Kingswood, Liisi Laaniste, Katherine Lachlan, Andrew Latchford, Ralitsa R Madsen, Sahar Mansour, Simeon R Mihaylov, Louwai Muhammed, Claire Oliver, Tom Pepper, Lettie E Rawlins, Ina Schim van der Loeff, Ata Siddiqui, Pooja Takhar, Katrina Tatton-Brown, Andrew R Tee, Priyanka Tibarewal, Charlotte Tye, Sila K Ultanir, Bart Vanhaesebroeck, Benjamin Zare, Deb K Pal, Joseph M Bateman.

  Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates key cellular processes including cell growth, autophagy and metabolism. Hyperactivation of the mTOR pathway causes a group of rare and ultrarare genetic diseases. mTOR pathway diseases have diverse clinical manifestations that are managed by distinct medical disciplines but share a common underlying molecular basis. There is a now a deep understanding of the molecular underpinning that regulates the mTOR pathway but effective treatments for most mTOR pathway diseases are lacking. Translating scientific knowledge into clinical applications to benefit the unmet clinical needs of patients is a major challenge common to many rare diseases. In this article we expound how mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients. We outline the germline and somatic mutations in the mTOR pathway that cause rare diseases and summarise the prevalence, genetic basis, clinical manifestations, pathophysiology and current treatments for each disease in this group. We describe the challenges and opportunities for progress in elucidating the underlying mechanisms, improving diagnosis and prognosis, as well as the development and approval of new therapies for mTOR pathway diseases. We illustrate the crucial role of patient public involvement and engagement in rare disease and mTOR pathway disease research. Finally, we explain how the mTOR Pathway Diseases node, part of the Research Disease Research UK Platform, will address these challenges to improve the understanding, diagnosis and treatment of mTOR pathway diseases.

Keywords:  AKT; Birt-Hogg-Dubé; Everolimus; PI3K; PTEN; Peutz-Jeghers; Rapamycin; Rare diseases; Tuberous sclerosis complex; mTOR

DOI:  https://doi.org/10.1186/s13023-025-03740-1
J Transl Med. 2025 May 25. 23(1): 583

The dual role of autophagy in cancer stem cells: implications for tumor progression and therapy resistance.

Haiqing Jia, Jing Wei, Wei Zheng, Zhuo Li.

  Cancer stem cells (CSCs) constitute a small yet crucial subgroup in tumors, known for their capacity to self-renew, differentiate, and promote tumor growth, metastasis, and resistance to therapy. These characteristics position CSCs as significant factors in tumor recurrence and unfavorable clinical results, emphasizing their role as targets for therapy. Autophagy, an evolutionarily preserved cellular mechanism for degradation and recycling, has a complex function in cancer by aiding cell survival during stress and preserving balance by eliminating damaged organelles and proteins. Although autophagy can hinder tumor growth by reducing genomic instability, it also aids tumor advancement, particularly in harsh microenvironments, highlighting its dual characteristics. Recent research has highlighted the complex interactions between autophagy and CSCs, showing that autophagy governs CSC maintenance, boosts survival, and aids in resistance to chemotherapy and radiotherapy. On the other hand, in specific situations, autophagy may restrict CSC growth by increasing differentiation or inducing cell death. These intricate interactions offer both obstacles and possibilities for therapeutic intervention. Pharmacological modulation of autophagy, via inhibitors like chloroquine or by enhancing autophagy when advantageous, has demonstrated potential in making CSCs more responsive to standard treatments. Nonetheless, applying these strategies in clinical settings necessitates a better understanding of context-dependent autophagy dynamics and the discovery of dependable biomarkers indicating autophagic activity in CSCs. Progressing in this area might unveil novel, accurate strategies to tackle therapy resistance, lessen tumor recurrence, and ultimately enhance patient outcomes.

Keywords:  Apoptosis; Autophagy; Cancer stem cells; Cell death; Drug resistance

DOI:  https://doi.org/10.1186/s12967-025-06595-z
Antioxidants (Basel). 2025 May 20. pii: 611. [Epub ahead of print]14(5):

c-Abl/TFEB Pathway Activation as a Common Pathogenic Mechanism in Lysosomal Storage Diseases: Therapeutic Potential of c-Abl Inhibitors.

Miguel V Guerra, Juan Castro, Antonio Moreno, Elisa Balboa, Juan J Marugan, Alejandra R Alvarez, Silvana Zanlungo.

  Lysosomal storage diseases (LSDs) are characterized by the accumulation of undegraded substrates within lysosomes, often associated with oxidative stress and impaired lysosomal function. In this study, we investigate the role of the c-Abl/TFEB pathway in different LSDs: Gaucher, Niemann-Pick type A (NPA), and Niemann-Pick type C (NPC). Our findings identify c-Abl activation (p-c-Abl) as a common pathogenic mechanism in these disorders. We demonstrate that c-Abl phosphorylates TFEB at Tyr173, leading to its cytoplasmic retention. Using pharmacological models of Gaucher, NPA and NPC in SH-SY5Y neuronal cells and HeLa cells, we assess the effects of the c-Abl inhibitors Imatinib and Neurotinib, as well as the antioxidant α-Tocopherol (α-TOH), on TFEB nuclear translocation and p-c-Abl protein levels. Additionally, we explore the effects of c-Abl inhibitors in cholesterol accumulation in LSDs neuronal models. Our results show that treatment with c-Abl inhibitors or α-TOH promotes TFEB nuclear translocation, enhances lysosomal clearance, and reduces cholesterol accumulation in all three LSD models. These findings highlight the c-Abl/TFEB pathway as a potential therapeutic target for LSDs and potentially other neurodegenerative disorders associated with lysosomal dysfunction.

Keywords:  Gaucher; Imatinib; Neurotinib; Niemann-Pick; c-Abl; lysosomal storage diseases; transcription factor EB; α-Tocopherol

DOI:  https://doi.org/10.3390/antiox14050611
Plant Sci. 2025 May 22. pii: S0168-9452(25)00195-5. [Epub ahead of print] 112577

Research progress on the autophagy gene ATG6 in planta.

Jiajun Wang, Shi Min Fu, Yan Zhou.

  Autophagy is a highly conserved intracellular degradation pathway in eukaryotes. Double-membrane autophagosomes engulf damaged organelles, misfolded proteins and pathogenic microorganisms and transport them to vacuoles (in yeast and plants) or lysosomes (in animals) for degradation to maintain cellular homeostasis. As a core regulatory component of class III PI3K-I and PI3K-II complexes, ATG6 is not only involved in autophagosome formation and vesicle trafficking, but also plays an important role in plant growth, development and stress responses. This paper reviews recent progress on the structural features, molecular functions and regulatory mechanisms of plant ATG6 in response to biotic and abiotic stresses, and discusses its potential application value in future stress-resistant plant breeding.

Keywords:  ATG6; Autophagy; Growth and development; Plants; Stress responses

DOI:  https://doi.org/10.1016/j.plantsci.2025.112577
EMBO Rep. 2025 May 28.

KEAP1 retention in phase-separated p62 bodies drives liver damage under autophagy-deficient conditions.

Shuhei Takada, Nozomi Shinomiya, Gaoxin Mao, Hikaru Tsuchiya, Tomoaki Koga, Satoko Komatsu-Hirota, Yu-Shin Sou, Manabu Abe, Elena Ryzhii, Michitaka Suzuki, Mitsuyoshi Nakao, Satoshi Waguri, Hideaki Morishita, Masaaki Komatsu.

  Phase-separated p62 bodies activate NRF2, a key transcription factor for antioxidant response, by sequestering KEAP1, which targets NRF2 for degradation. Although p62 bodies containing KEAP1 are degraded by autophagy, they accumulate in various liver disorders. Their precise disease role remains unclear. We show that excessive KEAP1 retention in p62 bodies and NRF2 activation are major causes of liver damage when autophagy is impaired. In mice with weakened or blocked p62-KEAP1 interactions, KEAP1 retention and NRF2 activation under autophagy-deficient conditions were suppressed. Transcriptome and proteome analyses reveal that p62 mutants unable to bind KEAP1 normalize the expression of NRF2 targets induced by defective autophagy. Autophagy deficiency causes organelle accumulation, especially of the ER, regardless of p62 mutation. Liver damage and hepatomegaly resulting from autophagy suppression markedly improved in mice carrying p62 mutants, particularly those with blocked KEAP1 binding. These findings highlight excessive KEAP1 retention in p62 bodies and defective organelle turnover as key drivers of liver pathology, underscoring the significance of phase separation in vivo.

Keywords:  KEAP1; Liquid–Liquid Phase Separation; NRF2; Stress Response; p62

DOI:  https://doi.org/10.1038/s44319-025-00483-9
Mol Cell. 2025 May 22. pii: S1097-2765(25)00408-3. [Epub ahead of print]

YTHDF1 differentiates the contributing roles of mTORC1 in aging.

Chenzhong Xu, Cong Yu, Jie Zhang, Zhen Zhang, Jin Zhang, Yuan Meng, Ming Wang, Minting Wen, Junhao Chen, Yuping Ning, Xinchun Chen, Jinke Gu, Wen Su, Baohua Liu.

  The mechanistic target of rapamycin (mTOR) serves as an essential hub in sensing metabolic stress and regulating aging, although the differential contributions of mTOR-regulated protein and cholesterol synthesis are unclear. Post-transcriptional modifications of mRNAs, such as N6-methyladenosine (m6A), occur rapidly in response to acute environmental changes to maintain tissue homeostasis. Here, we showed that loss of YTH m6A RNA-binding protein 1 (YTHDF1) accelerated murine aging. Mechanistically, YTHDF1 is anchored to the lysosome surface by lysosome-associated membrane protein (LAMP2), whereby it recruits tuberous sclerosis complex (TSC2) to inhibit mTOR complex 1 (mTORC1). Ythdf1 loss activated mTORC1-sterol regulatory element-binding protein 2 (SREBP2)-axis-mediated cholesterol biosynthesis but not m6A-reader-regulated protein translation. Rapamycin restored murine healthspan in contrast to the maximum lifespan shortening caused by Ythdf1 depletion. Our data reveal an m6A-independent function of YTHDF1, which differentiates the contributing roles of mTORC1 in the regulation of aging.

Keywords:  SREBP2; TSC2; YTHDF1; aging; m6A; mTORC1; rapamycin

DOI:  https://doi.org/10.1016/j.molcel.2025.05.003
Biomolecules. 2025 May 16. pii: 728. [Epub ahead of print]15(5):

Recovery of Lysosomal Acidification and Autophagy Flux by Attapulgite Nanorods: Therapeutic Potential for Lysosomal Disorders.

Yuanjing Hao, Xinru Fan, Xiaodan Huang, Zhaoying Li, Zhiyuan Jing, Guilong Zhang, Yuxue Xu, Na Zhang, Pengfei Wei.

  Dysfunction of the lysosome and autophagy-lysosome pathway is closely associated with various diseases, such as neurodegenerative diseases, non-alcoholic fatty liver disease (NAFLD), etc. Additionally, chloroquine is a clinically widely used drug for treating malaria and autoimmune diseases, but long-term or high-dose administration may lead to significant toxic side effects. Attapulgite (ATT), a natural nanomaterial with excellent adsorption capacity and biocompatibility, herein demonstrated a novel biological function in regulating the lysosomal and autophagy-lysosome pathway. ATT could be effectively internalized into lysosome-related acidic compartments. Further study revealed that ATT could restore lysosomal pH, activate cathepsin D, alleviate autophagy blockage in chloroquine-treated cells, and reduce chloroquine-elicited cell death. In a cell model related to Huntington's disease, treatment with ATT reinforced the degradation of the mutant huntingtin proteins by increasing cathepsin D maturation and autophagy flux. ATT could also promote lipid droplet clearance in hepatocytes with palmitic acid-induced steatosis, reduce hepatic lipid accumulation, and improve fasting blood glucose in high-fat-diet-induced NAFLD mice. These findings establish ATT as a lysosomal modulator, providing a foundation for its therapeutic potential in mitigating the adverse effects associated with long-term chloroquine use, especially improving neurodegenerative and metabolic disorders.

Keywords:  attapulgite; autophagy flux; lysosomes; mutant huntingtin; neurodegenerative diseases; non-alcoholic fatty liver disease

DOI:  https://doi.org/10.3390/biom15050728
Cell Death Discov. 2025 May 27. 11(1): 254

CO confers neuroprotection via activating the PERK-calcineurin pathway and inhibiting necroptosis.

Jeongmin Park, LiHua Jin, Hyun-Chul Song, Yingqing Chen, Eun Young Jang, Gyu Hwan Park, Chae Ha Yang, Stefan W Ryter, Jeong Woo Park, Min Zheng, Yeonsoo Joe, Hun Taeg Chung.

Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), are marked by progressive neuronal loss. Regulated cell death programs (i.e., necroptosis) as well as homeostatic mechanisms (i.e., autophagy) can modulate disease pathogenesis. Low-dose carbon monoxide (CO) has been shown to activate cytoprotective responses in various models of tissue injury. Our study investigates the protective roles of CO in neurodegenerative disease through the modulation of necroptosis and autophagy programs. We found that CO activates the Protein kinase RNA (PKR)-like ER kinase (PERK) branch of the unfolded protein response (UPR) and the calcineurin pathway, leading to significant neuroprotective effects in cellular and mouse models of PD. CO-induced PERK activation promotes the nuclear translocation of transcription factor EB (TFEB). Subsequently, TFEB enhances autophagy through increased expression of autophagy-related genes and inhibits necroptosis by suppressing the phosphorylation and oligomerization of Mixed Lineage Kinase Domain-Like Pseudokinase (MLKL), a key necroptosis regulator. Furthermore, CO enhances the expression of Beclin 1, which inhibits necroptosis, independently of its autophagic function, by regulating MLKL oligomerization. Our findings suggest that modulation of the PERK-calcineurin pathway and downstream activation of cellular defense mechanisms by CO may serve as a promising therapeutic approach to mitigate neuronal loss in neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41420-025-02530-9
Curr Opin Neurobiol. 2025 May 24. pii: S0959-4388(25)00085-6. [Epub ahead of print]93 103054

Macroautophagy at the service of synapses.

Erin Wosnitzka, Lisa Gambarotto, Vassiliki Nikoletopoulou.

Post-mitotic and highly polarized neurons are dependent on the fitness of their synapses, which are often found a long distance away from the soma. How the synaptic proteome is maintained, dynamically reshaped, and continuously turned over is a topic of intense investigation. Autophagy, a highly conserved, lysosome-mediated degradation pathway has emerged as a vital component of long-term neuronal maintenance, and now more specifically of synaptic homeostasis. Here, we review the most recent findings on how autophagy undergoes both dynamic and local regulation at the synapse, and how it contributes to pre- and post-synaptic proteostasis and function. We also discuss the insights and open questions that this new evidence brings.

DOI: https://doi.org/10.1016/j.conb.2025.103054
Cells. 2025 05 20. pii: 749. [Epub ahead of print]14(10):

Extracellular Vesicles in the Crosstalk of Autophagy and Apoptosis: A Role for Lipid Rafts.

Agostina Longo, Valeria Manganelli, Roberta Misasi, Gloria Riitano, Tuba Rana Caglar, Elena Fasciolo, Serena Recalchi, Maurizio Sorice, Tina Garofalo.

  Autophagy and apoptosis are two essential mechanisms regulating cell fate. Although distinct, their signaling pathways are closely interconnected through various crosstalk mechanisms. Lipid rafts are described to act as both physical and functional platforms during the early stages of autophagic and apoptotic processes. Only recently has a role for lipid raft-associated molecules in regulating EV biogenesis and release begun to emerge. In particular, lipids of EV membranes are essential components in conferring stability to these vesicles in different extracellular environments and/or to facilitate binding or uptake into recipient cells. In this review we highlight these aspects, focusing on the role of lipid molecules during apoptosis and secretory autophagy pathways. We describe the molecular machinery that connects autophagy and apoptosis with vesicular trafficking and lipid metabolism during the release of EVs, and how their alterations contribute to the development of various diseases, including autoimmune disorders and cancer. Overall, these findings emphasize the complexity of autophagy/apoptosis crosstalk and its key role in cellular dynamics, supporting the role of lipid rafts as new therapeutic targets.

Keywords:  apoptosis; autophagy; exosomes; extracellular vesicles; lipid rafts

DOI:  https://doi.org/10.3390/cells14100749
Front Pharmacol. 2025 ;16 1562845

Dysregulation of autophagy during photoaging reduce oxidative stress and inflammatory damage caused by UV.

Zhongsong Zhang, Run Tan, Zuanyu Xiong, Yanyan Feng, Long Chen.

  Photoaging, the premature aging of skin due to chronic ultraviolet (UV) exposure, is a growing concern in dermatology and cosmetic science. While UV radiation is known to induce DNA damage, oxidative stress, and inflammation in skin cells, recent research unveils a promising countermeasure: autophagy. This review explores the intricate relationship between autophagy and photoaging, highlighting how this cellular recycling process can mitigate UV-induced damage. We begin by examining the differential impacts of UVA and UVB radiation on skin cells and the role of oxidative stress in accelerating photoaging. Next, we delve into the molecular mechanisms of autophagy, including its various forms and regulatory pathways. Central to this review is the discussion of autophagy's protective functions, such as the clearance of damaged organelles and proteins, and its role in maintaining genomic integrity. Furthermore, we address the current challenges in harnessing autophagy for therapeutic purposes, including the need for selective autophagy inducers and a deeper understanding of its context-dependent effects. By synthesizing recent advancements and proposing future research directions, this review underscores the potential of autophagy modulation as a novel strategy to prevent and treat photoaging. This comprehensive analysis aims to inspire further investigation into autophagy-based interventions, offering new hope for preserving skin health in the face of environmental stressors.

Keywords:  ROS; UV; autophagy; photoaging; skin aging

DOI:  https://doi.org/10.3389/fphar.2025.1562845
Pharmaceuticals (Basel). 2025 May 01. pii: 671. [Epub ahead of print]18(5):

Advances in Targeted Autophagy Modulation Strategies to Treat Cancer and Associated Treatment-Induced Cardiotoxicity.

Lauren A Ling, Asma Boukhalfa, Andrew H Kung, Vicky K Yang, Howard H Chen.

  Autophagy, an evolutionarily conserved process, plays an important role in cellular homeostasis and human diseases. Cardiovascular dysfunction, which presents during cancer treatment or in cancer-free individuals years after treatment, is a growing clinical challenge. Millions of cancer survivors and patients face an unpredictable risk of developing cardiotoxicity. Cardiotoxicity due to cancer treatment, as well as cancer progression, has been linked to autophagy dysregulation. Modulating autophagy has been further proposed as a therapeutic treatment for both cancer and cardiovascular disorders. The safe and effective use of autophagy modulation as a cardioprotective strategy during cancer treatment especially requires careful consideration and experimentation to minimize the impact on cancer treatment. We focus here on recent advances in targeted autophagy modulation strategies that utilize interdisciplinary approaches in biomedical sciences and are potentially translatable to treat cardiotoxicity and improve cancer treatment outcomes. This review highlights non-small molecule autophagy modulators to enhance targeted therapy, nanomedicine for autophagy modulation and monitoring, and in vitro models and future experiments needed to bring novel autophagy discoveries from basic research to clinical translation.

Keywords:  apoptosis; autophagy; cardio-oncology; cardioprotection; nanotechnology

DOI:  https://doi.org/10.3390/ph18050671
J Biol Chem. 2025 May 24. pii: S0021-9258(25)02142-8. [Epub ahead of print] 110292

UPS10 inhibits the degradation of α-synuclein, a pathogenic factor associated with Parkinson's disease, by inhibiting chaperone-mediated autophagy.

Sergei Anisimov, Masahiko Takahashi, Taichi Kakihana, Yoshinori Katsuragi, Junya Sango, Takayuki Abe, Masahiro Fujii.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, particularly in the substantia nigra of the brain. α-Synuclein is a major causative factor in both familial and sporadic forms of PD, and its protein aggregates play critical roles in neuronal cell death and PD pathogenesis. This study explored the role of ubiquitin-specific protease 10 (USP10) in the regulation of α-synuclein in neuronal cells. Knockdown of USP10 (USP10-KD) in SH-SY5Y neuronal cells led to a reduction in α-synuclein levels, which was reversed by inhibiting chaperone-mediated autophagy (CMA) through LAMP2A depletion, a protein essential for CMA. A novel CMA reporter with a specific CMA degradation motif further demonstrated that USP10-KD activated CMA in neuronal cells. In addition, USP10 overexpression increased the levels of both wild-type and five PD-associated α-synuclein mutants, whereas a deubiquitinase-deficient USP10 mutant did not increase α-synuclein levels. This study provides new insights into the mechanisms that regulate α-synuclein proteostasis and highlights USP10 as a promising drug target for PD.

Keywords:  Parkinson’s disease; USP10; α-synuclein; сhaperone-mediated autophagy

DOI:  https://doi.org/10.1016/j.jbc.2025.110292
Nat Commun. 2025 May 27. 16(1): 4909

Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.

Yao Zhang, Peng Ma, Saifei Wang, Shuxin Chen, Hansong Deng.

Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa2+) levels were elevated while mitochondrial calcium (MitoCa2+) levels were decreased and associated with metabolic shift in aged intestinal stem cells (ISCs) of Drosophila. How MitoCa2+ was decoupled from the intracellular calcium network and whether the reduction of MitoCa2+ drives ISC aging, however, remains unresolved. Here, we show that genetically restoring MitoCa2+ can reverse ISC functional decline and promote intestinal homeostasis by activating autophagy in aged flies. Further studies indicate that MitoCa2+ and Mitochondria-ER contacts (MERCs) form a positive feedback loop via IP3R to regulate autophagy independent of AMPK. Breakdown of this loop is responsible for MitoCa2+ reduction and ISC dysfunction in aged flies. Our results identify a regulatory module for autophagy initiation involving calcium crosstalk between the ER and mitochondria, providing a strategy to treat aging and age-related diseases.

DOI: https://doi.org/10.1038/s41467-025-60196-4
J Biochem. 2025 May 29. pii: mvaf027. [Epub ahead of print]

Autophagy promotes the acquisition of genotoxic resistance in cancer cells in a paracrine manner via upregulation of PLK1-RAD9A axis.

Masae Ikura, Takuma Shiraki, Tsuyoshi Ikura, Kanji Furuya.

  Autophagy suppresses tumorigenesis in normal cells, but in established tumors, it can promote tumor progression, particularly by enhancing resistance to stress. However, the mechanism underlying this tumor-promoting function remains unclear. To investigate this, we adopted an interdisciplinary approach combining database analysis with experimental validation. Specifically, by classifying the autophagy-related genes using AutoML analysis on their expression patterns in the COSMIC database, we identified an autophagy subnetwork that correlated with the PLK1-RAD9A axis, a pathway we had previously linked to genotoxic resistance. Cell-based experiments confirmed that autophagy enhanced PLK1 expression at both the transcriptional and translational levels, facilitating genotoxic resistance. Notably, in stressed S-phase cells, we found that PLK1 expression levels varied among individual cells, yet overall cell population acquired genotoxin resistance. The genotoxin resistance in the cell population with heterogeneous PLK1 expression was driven by autophagy by facilitating the secretion of currently unidentified factors, likely by switching funtion of RAD9A from DNA checkpoint to substance secretion. Together our data demonstrate that intra-tumor heterogeneity contributes to the malignant features of tumors through an autophagy-PLK-RAD9A axis that promotes intercellular communication via secretion. (180 words).

Keywords:  DNA replication checkpoint; autophagy; cancer; genotoxic resistance; radiation

DOI:  https://doi.org/10.1093/jb/mvaf027
Int J Mol Sci. 2025 May 15. pii: 4742. [Epub ahead of print]26(10):

The Role of Intermittent Fasting in the Activation of Autophagy Processes in the Context of Cancer Diseases.

Waleria Wolska, Izabela Gutowska, Agata Wszołek, Wojciech Żwierełło.

  Intermittent fasting (IF) is a dietary approach that influences key metabolic pathways, including autophagy-a crucial mechanism in maintaining cellular homeostasis. Autophagy plays a dual role in oncogenesis, acting both as a tumor suppressor and a survival mechanism under metabolic stress. IF has shown potential for reducing cancer risk and enhancing therapeutic efficacy by sensitizing tumor cells to chemotherapy and radiotherapy. However, its effects depend heavily on the type and stage of cancer. Potential risks, such as excessive weight loss and malnutrition, require careful evaluation. Further clinical studies are needed to optimize IF protocols as adjuncts to cancer therapy. This review discusses autophagy mechanisms induced by IF, their therapeutic implications in oncology, and the limitations of this dietary strategy.

Keywords:  autophagy; calorie restriction; cancer; diets; intermittent fasting

DOI:  https://doi.org/10.3390/ijms26104742
Physiol Rep. 2025 May;13(10): e70381

Loss of hepatic autophagy induces α-cell proliferation through impaired glutamine-dependent gluconeogenesis.

Jesse N Velasco-Silva, Joseph L Wilkerson, Daniela Ramos, Hayden K Low, Faith Bowman, Kimberley J Evason, Sihem Boudina, William L Holland, Gregory S Ducker.

  Autophagy, the highly conserved process of protein and organelle degradation, is suppressed in the liver by obesity and metabolic dysfunction-associated fatty liver disease and associated with the development of insulin resistance. We generated adult liver-inducible ATG3 knockout mice (Atg3iLKO) to characterize pathways linking hepatic autophagy with metabolic homeostasis. Genetic loss of hepatic autophagy leads to a reduction in 16-h fasted glucose levels, a decrease in endogenous glucose production rates, and an increase in serum amino acids across the fed and fasted states. These changes collectively reflect a loss of hepatic gluconeogenic enzyme activity and not a general inability to degrade amino acids in the liver. Increased circulating glutamine levels resulting from this are associated with an induction of α-cell hyperplasia, leading to constitutively elevated glucagon levels. However, the loss of hepatic gluconeogenesis renders these animals highly glucagon resistant. Collectively, our data demonstrate that loss of hepatic autophagy is sufficient to activate the hepatic α-islet cell axis, leading to hyperglucagonemia with impaired glucose production.

Keywords:  alpha cell; autophagy; glucose; hyperglucagonemia; liver metabolism

DOI:  https://doi.org/10.14814/phy2.70381
Nat Commun. 2025 May 27. 16(1): 4920

WNK1 signalling regulates amino acid transport and mTORC1 activity to sustain acute myeloid leukaemia growth.

Shunlei Duan, Karl Agger, Jan-Erik Messling, Koutarou Nishimura, Xuerui Han, Isabel Peña-Rømer, Pavel Shliaha, Helene Damhofer, Max Douglas, Manas Kohli, Akos Pal, Yasmin Asad, Aaron Van Dyke, Raquel Reilly, Robert Köchl, Victor L J Tybulewicz, Ronald C Hendrickson, Florence I Raynaud, Paolo Gallipoli, George Poulogiannis, Kristian Helin.

The lack of curative therapies for acute myeloid leukaemia (AML) remains an ongoing challenge despite recent advances in the understanding of the molecular basis of the disease. Here we identify the WNK1-OXSR1/STK39 pathway as a previously uncharacterised dependency in AML. We show that genetic depletion and pharmacological inhibition of WNK1 or its downstream phosphorylation targets OXSR1 and STK39 strongly reduce cell proliferation and induce apoptosis in leukaemia cells in vitro and in vivo. Furthermore, we show that the WNK1-OXSR1/STK39 pathway controls mTORC1 signalling via regulating amino acid uptake through a mechanism involving the phosphorylation of amino acid transporters, such as SLC38A2. Our findings underscore an important role of the WNK1-OXSR1/STK39 pathway in regulating amino acid uptake and driving AML progression.

DOI: https://doi.org/10.1038/s41467-025-59969-8
JCI Insight. 2025 May 29. pii: e187904. [Epub ahead of print]

mTOR signaling regulates the development of airway mucous cell metaplasia associated with severe asthma.

Katrina M Kudrna, Luis F Vilches, Evan M Eilers, Shailendra K Maurya, Steven L Brody, Amjad Horani, Kristina L Bailey, Todd A Wyatt, John D Dickinson.

  In asthma, airway epithelial remodeling is characterized by aberrant goblet cell metaplastic differentiation accompanied by epithelial cell hyperplasia and hypertrophy. These pathologic features in severe asthma indicate a loss of control of proliferation, cell size, differentiation, and migration. mTOR is a highly conserved pathway that regulates protein synthesis, cell size, and proliferation. We hypothesized that the balance between mTOR and autophagy regulates mucous cell metaplasia. Airways from individuals with severe asthma showed increased mTOR signaling by RPS6 phosphorylation, which was reproduced using an IL-13-activated model of primary human airway epithelial cells (hAECs). mTOR inhibition by rapamycin led to a decrease of IL-13-mediated cell hypertrophy, hyperplasia, and MUC5AC mucous metaplasia. BrdU labeling during IL-13-induced mucous metaplasia confirmed that mTOR was associated with increased basal-to-apical hAEC migration. mTOR activation by genetic deletion of Tsc2 in cultured mouse AECs increased IL-13-mediated hyperplasia, hypertrophy, and mucous metaplasia. Transcriptomic analysis of IL-13-stimulated hAEC identified mTOR-dependent expression of genes associated with epithelial migration and cytoskeletal organization. In summary, these findings point to IL-13-dependent and independent roles of mTOR signaling in the development of pathogenic epithelial changes contributing to airway obstruction in severe asthma.

Keywords:  Asthma; Autophagy; Cell biology; Cell migration/adhesion; Pulmonology

DOI:  https://doi.org/10.1172/jci.insight.187904
FASEB J. 2025 Jun 15. 39(11): e70663

A Novel Function of NaV Channel β3 Subunit in Endothelial Cell Alignment Through Autophagy Modulation.

Léa Réthoré, Anne-Laure Guihot, Linda Grimaud, Coralyne Proux, Benjamin Barré, François Guillonneau, Catherine Guette, Alice Boissard, Cécile Henry, Jérôme Cayon, Rodolphe Perrot, Daniel Henrion, Christian Legros, Claire Legendre.

  Endothelial cells (EC) play a pivotal role in vascular homeostasis. By sensing shear stress generated by blood flow, EC endorse vasculoprotection through mechanotransduction signaling pathways. Various ion channels are involved in mechanosignaling, and here, we investigated the endothelial voltage-gated Na+ channels (NaV channels), since their mechanosensitivity has been previously demonstrated in cardiomyocytes. First, we showed that EC from aorta (TeloHAEC) behave as EC from umbilical vein (HUVEC) under laminar shear stress (LSS). For both EC models, cell alignment and elongation occurred with the activation of the KLF2/KLF4 atheroprotective signaling pathways. We found that LSS decreased the expression of SCN5A, encoding NaV1.5, while LSS increased that of SCN3B, encoding NaVβ3. We demonstrated that the KLF4 transcription factor is involved in SCN3B expression under both static and LSS conditions. Interestingly, SCN3B silencing impaired EC alignment induced by LSS. The characterization of NaVβ3 interactome by coimmunoprecipitation and proteomic analysis revealed that mTOR, implicated in autophagy, binds to NaVβ3. This result was evidenced by the colocalization between NaVβ3 and mTOR inside cells. Moreover, we showed that SCN3B silencing led to the decrease in LC3B expression and the number of LC3B positive autophagosomes. Furthermore, we showed that NaVβ3 is retained within the cell and colocalized with LAMP1 and LC3B. Finally, we found that resveratrol, a stimulating-autophagy and vasculoprotective molecule, induced KLF4 together with NaVβ3 expression. Altogether, our findings highlight a novel role of NaVβ3 in endothelial function and cell alignment as an actor in shear stress vasculoprotective intracellular pathway through autophagy modulation.

Keywords:   SCN3B ; NaVβ3; autophagy; endothelial cell; mechanosignaling; shear stress

DOI:  https://doi.org/10.1096/fj.202401558RR
Mol Cancer. 2025 May 26. 24(1): 152

NAP1L1 degradation by FBXW7 reduces the deubiquitination of HDGF-p62 signaling to stimulate autophagy and induce primary cisplatin chemosensitivity in nasopharyngeal carcinoma.

Bin Gong, Yahui Liu, Weiwei Yan, Chao Cheng, Huiling Yang, Jiyu Huang, Qing Liu, Yuyan Liu, Jiankang Guo, Xiaojie Deng, Beixian Zhou, Dayong Zheng, Xiong Liu, Zhen Liu, Weiyi Fang.

  Nucleosome assembly protein 1-like 1 (NAP1L1) has been implicated in promoting tumor cell proliferation. However, its role in regulating autophagy in tumors, including nasopharyngeal carcinoma (NPC), remains unclear. In this study, we observed that autophagy-inducing agents reduced NAP1L1 protein levels without affecting its mRNA expression. Reduced NAP1L1 enhanced autophagosome formation and maturation, thereby promoting cisplatin (DDP) chemosensitivity in both in vitro and in vivo NPC models. Mechanistically, reduced NAP1L1 impaired the recruitment of ubiquitin-specific protease 14 (USP14), limiting the deubiquitination of heparin-binding growth factor (HDGF) and decreasing HDGF protein levels. In turn, reduced HDGF suppressed USP14-mediated p62 deubiquitination, leading to further declines in p62 protein levels. Notably, the F-box and WD repeat domain-containing protein 7 (FBXW7), an inhibitory E3 ubiquitin ligase, directly interacted with and ubiquitinated NAP1L1, promoting its degradation. This degradation triggered NPC autophagy and enhanced DDP chemosensitivity by disrupting NAP1L1-induced HDGF/p62 signaling. Clinically, NAP1L1 protein expression was inversely correlated with FBXW7 levels in NPC tissue samples. Patients exhibiting high NAP1L1 and low FBXW7 levels had the poorest DDP chemosensitivity and survival outcomes. Our findings demonstrate that FBXW7-mediated NAP1L1 degradation suppresses HDGF-p62 signaling, thereby inducing autophagy and enhancing DDP chemosensitivity. These results underscore the potential of NAP1L1 and FBXW7 as therapeutic targets for NPC treatment.

Keywords:  Autolysosomes; Autophagosomes; Chemosensitivity; E3 ubiquitin ligase; Ubiquitin degradation

DOI:  https://doi.org/10.1186/s12943-025-02349-z
Cells. 2025 05 15. pii: 721. [Epub ahead of print]14(10):

Misregulation of the Ubiquitin-Proteasome System and Autophagy in Muscular Dystrophies Associated with the Dystrophin-Glycoprotein Complex.

Manuela Bozzi, Francesca Sciandra, Maria Giulia Bigotti, Andrea Brancaccio.

  The stability of the sarcolemma is severely impaired in a series of genetic neuromuscular diseases defined as muscular dystrophies. These are characterized by the centralization of skeletal muscle syncytial nuclei, the replacement of muscle fibers with fibrotic tissue, the release of inflammatory cytokines, and the disruption of muscle protein homeostasis, ultimately leading to necrosis and loss of muscle functionality. A specific subgroup of muscular dystrophies is associated with genetic defects in components of the dystrophin-glycoprotein complex (DGC), which plays a crucial role in linking the cytosol to the skeletal muscle basement membrane. In these cases, dystrophin-associated proteins fail to correctly localize to the sarcolemma, resulting in dystrophy characterized by an uncontrolled increase in protein degradation, which can ultimately lead to cell death. In this review, we explore the role of intracellular degradative pathways-primarily the ubiquitin-proteasome and autophagy-lysosome systems-in the progression of DGC-linked muscular dystrophies. The DGC acts as a hub for numerous signaling pathways that regulate various cellular functions, including protein homeostasis. We examine whether the loss of structural stability within the DGC affects key signaling pathways that modulate protein recycling, with a particular emphasis on autophagy.

Keywords:  autophagy; dystroglycan; dystroglycanopathies; dystrophin; proteasome degradation

DOI:  https://doi.org/10.3390/cells14100721
Biology (Basel). 2025 May 06. pii: 507. [Epub ahead of print]14(5):

Targeting Methionine Metabolism Reveals AMPK-SAMTOR Signaling as a Therapeutic Vulnerability in Prostate Cancer.

Serdar Arisan, Ayyuce Sever, Pinar Obakan-Yerlikaya, Elif Damla Arisan, Pinar Uysal-Onganer.

  Prostate cancer (PCa) is not only one of the most diagnosed malignancies in men but also a leading cause of cancer-related mortality globally. PCa exhibits unique metabolic dependencies, particularly on lipids and glutamine, unlike many solid tumors, rather than glycolysis. Methionine metabolism plays a crucial role in these metabolic pathways, contributing to polyamine biosynthesis, DNA methylation, and cellular signaling processes. Here, we demonstrate that methionine deprivation induces selective vulnerability in AMPK-deficient PC3 PCa cells by disrupting SAMTOR-mTOR signaling and triggering oxidative stress, lipid depletion, and autophagic responses. Through functional and proteomic analyses, we show that SAMTOR directly interacts with p-AMPK and modulates cell fate under methionine-limited conditions. Our findings establish a mechanistic link between methionine sensing and metabolic stress signaling in PCa, offering a new avenue for targeted intervention.

Keywords:  SAMTOR; autophagy; mTOR; methionine; prostate cancer

DOI:  https://doi.org/10.3390/biology14050507
Nat Aging. 2025 May 28.

The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan.

Lisonia Gkioni, Tobias Nespital, Maarouf Baghdadi, Carolina Monzó, Jitin Bali, Taim Nassr, Anna Lena Cremer, Andreas Beyer, Joris Deelen, Heiko Backes, Sebastian Grönke, Linda Partridge.

Suppression of the insulin-IGF-mTORC1-Ras network ameliorates aging in animals. Many drugs have targets in the network because of its roles in cancer and metabolic disease and are candidates for repurposing as geroprotectors. Rapamycin, an established geroprotective drug, blocks mTORC1 signaling, and trametinib inhibits the Ras-MEK-ERK pathway. In this study, we assessed survival and health of male and female mice treated with trametinib, rapamycin or their combination. We show here that trametinib treatment extended lifespan in both sexes and that its combination with rapamycin was additive. Combination treatment reduced liver tumors in both sexes and spleen tumors in male mice, blocked the age-related increase in brain glucose uptake and strongly reduced inflammation in brain, kidney, spleen and muscle and circulating levels of pro-inflammatory cytokines. We conclude that trametinib is a geroprotector in mice and that its combination with rapamycin is more effective than either drug alone, making the combination a candidate for repurposing as a gerotherapy in humans.

DOI: https://doi.org/10.1038/s43587-025-00876-4
Front Endocrinol (Lausanne). 2025 ;16 1541714

Research on the role and mechanism of the PI3K/Akt/mTOR signalling pathway in osteoporosis.

Chuanlong Liu, Jianqiang Zhang, Ziyu Ye, Ji Luo, Bing Peng, Zhexiang Wang.

  Osteoporosis is a systemic metabolic bone disease characterised mainly by reduced bone mass, bone microstructure degradation, and loss of bone mechanical properties. As the world population ages, more than 200 million people worldwide suffer from the pain caused by osteoporosis every year, which severely affects their quality of life. Moreover, the prevalence of osteoporosis continues to increase. The pathogenesis of osteoporosis is highly complex and is closely related to apoptosis, autophagy, oxidative stress, the inflammatory response, and ferroptosis. The PI3K/Akt/mTOR signalling pathway is one of the most crucial intracellular signal transduction pathways. This pathway is not only involved in bone metabolism and bone remodelling but also closely related to the proliferation and differentiation of osteoblasts, osteoclasts, and bone marrow mesenchymal stem cells. Abnormal activation or inhibition of the PI3K/Akt/mTOR signalling pathway can disrupt the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, ultimately leading to the development of osteoporosis. This review summarises the molecular mechanisms by which the PI3K/Akt/mTOR signalling pathway mediates five pathological mechanisms, namely, apoptosis, autophagy, oxidative stress, the inflammatory response, and ferroptosis, in the regulation of osteoporosis, aiming to provide a theoretical basis for the development of novel and effective therapeutic drugs and intervention measures for osteoporosis prevention and treatment.

Keywords:  Akt; PI3K; mTOR; osteoporosis; pathological mechanisms

DOI:  https://doi.org/10.3389/fendo.2025.1541714
Acta Neuropathol Commun. 2025 May 24. 13(1): 115

Evaluation of aggrephagy markers in myofibrillar myopathies.

Eliana Iannibelli, Alessandra Ruggieri, Antonello Maruotti, Franco Salerno, Marta Cheli, Alessandra Carnazzi, Lucia Nicolini De Gaetano, Giorgia Riolo, Sara Bortolani, Pietro Riguzzi, Sara Vianello, Gioia Merlonghi, Luca Bello, Matteo Garibaldi, Massimiliano Filosto, Stefano Carlo Previtali, Giorgio Tasca, Gaetano Vattemi, Paola Tonin, Elena Pegoraro, Sara Gibertini, Lorenzo Maggi.

  Myofibrillar Myopathies (MFMs) are a growing group of muscular disorders genetically determined, whose diagnosis is based on histological features as myofibrillar degeneration, Z-disk disorganization and protein aggregates' accumulation. Protein aggregates that do not fit the proteasome's narrow pore are targeted for removal via a specialized form of autophagy, called aggrephagy. Our study aims to investigate the potential pathogenic role of aggrephagy in 52 muscle samples from an Italian MFM multicentric cohort. We measured, the percentage of positive areas of key aggrephagy proteins by immunofluorescence staining, of sequestosome 1 (p62/SQSTM1), Neighbor of BRCA1 Gene 1 (NBR1), and ubiquitinated proteins (FK2) in 11 DES-, 6 DNAJB6-, 5 FLNC-, 18 MYOT- and 12 TTN-mutated patients. We showed that all aggrephagy markers are increased in these patients, regardless of the mutated genes, suggesting a possible common pathomechanism; no positive signal was found in healthy, age-matched controls. We analyzed the association between positivity levels of these markers, measured as percentage of positive areas, and selected clinical features utilizing generalized linear mixed models with gamma distribution as the probability model and center-specific random effects to better capture possible heterogeneity across participating centers. Our findings indicate significant associations between levels of p62, NBR1, and FK2 with age at biopsy (p62 and NBR1 p-values < 0.001, FK2 p-value < 0.05), age of onset (p62 and NBR1 p-values < 0.001, FK2 p-value < 0.01) and disease severity through Walton & Gardner-Medwin (WGM) score at biopsy (all p-values < 0.001) and at the last visit (all p-values < 0.05). Noteworthy, the aggrephagic pathway is mostly activated in MYOT-mutated patients compared to the other subgroups. Moreover, the association between aggrephagy and WGM score at biopsy is stronger in this subgroup. Overall, our study emphasizes the role of aggrephagy in MFMs across all patients, and its association with specific clinical parameters.

Keywords:  Clinical association; Genetic rare diseases; Myofibrillar alterations; Protein aggregation

DOI:  https://doi.org/10.1186/s40478-025-02041-9
Autophagy. 2025 May 25.

Unveiling EXOC4/SEC8: a key player in enhancing antiviral immunity by inhibiting the FBXL19-STING1-SQSTM1 signaling axis.

Lin Wang, Peili Hou, Wenqing Ma, Rong Jin, Xinxin Wei, Xingyu Li, Hongbin He, Hongmei Wang.

  As a core aptamer for anti-DNA viral immunity, STING1 (stimulator of interferon response cGAMP interactor 1) is tightly regulated to ensure the proper functioning of the natural antiviral immune response. However, many mechanisms underlying the regulation of STING1 remain largely unknown. In this study, we identify EXOC4/SEC8 (exocyst complex component 4) as a novel positive regulator of DNA virus-triggered type I interferon signaling responses through stabilizing STING1, thereby inhibiting DNA viral replication. Mechanistically, EXOC4 suppresses K27-linked ubiquitination of STING1 at K338, K347, and K370 catalyzed by the E3 ligase FBXL19 (F-box and leucine rich repeat protein 19), thereby preventing ubiquitinated-STING1 from recognition by SQSTM1 (sequestosome 1) for autophagic degradation. Importantly, mice conditionally knocked out for Exoc4/Sec8 are more susceptible to herpes simplex virus type 1 (HSV-1) infection and exhibit more severe lung pathology compared to control mice. This further confirms the important role of EXOC4/SEC8 in antiviral natural immunity. Taken together, our study reveals the importance of EXOC4/SEC8 in promoting STING1-centered antiviral natural immunity and highlights its potential as an anti-DNA viral therapeutic target.

Keywords:  Autophagic degradation; DNA viral infection; EXOC4; FBXL19; IFN-I; STING1

DOI:  https://doi.org/10.1080/15548627.2025.2511077