bims-auttor 2025-03-30 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–03–30
63 papers selected by
Viktor Korolchuk, Newcastle University

TGFB signaling induces mitophagy via PLSCR3-mediated cardiolipin externalization in conjunction with a BNIP3L/NIX-, BNIP3-, and FUNDC1-dependent mechanism.
Autophagic stagnation: a key mechanism in kidney disease progression linked to aging and obesity.
Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate.
The emerging roles of S-acylation in autophagy.
T16G12.6/IMPORTIN 13-mediated cytoplasm-to-nucleus transport of the THAP transcription factor LIN-15B controls autophagy and lysosome function in C. elegans.
Methamphetamine and Methamphetamine-Induced Neuronal Exosomes Modulate the Activity of Rab7a via PTEN to Exert an Influence on the Disordered Autophagic Flux Induced in Neurons.
Inhibition of Salt-Inducible Kinase 2 Protects Motor Neurons From Degeneration in ALS by Activating Autophagic Flux and Enhancing mTORC1 Activity.
Activated mTORC1 signaling pathway aggravates cisplatin induced oxidative damage by inhibiting autophagy in mouse cochlear hair cells.
CDX1 improves nicotine induced cardiac fibroblasts activation and cardiomyocyte hypertrophy by alleviating autophagic flux impairment through modulation of LAPTM4B.
The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease.
The inducible role of autophagy in cell death: emerging evidence and future perspectives.
The ER-phagy receptor FAM134B is targeted by Salmonella Typhimurium to promote infection.
Monitoring Autophagy in Human Aging: Key Cell Models and Insights.
ATP6AP1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy.
Mycobacterium tuberculosis phagosome Ca2+ leakage triggers multimembrane ATG8/LC3 lipidation to restrict damage in human macrophages.
Hippocampal Inhibitory Interneuron-Specific DREADDs Treatment Alters mTORC1-4E-BP Signaling and Impairs Memory Formation.
(-)-Epicatechin Rescues Memory Deficits by Activation of Autophagy in a Mouse Model of Tauopathies.
ESCRT iii-mediated lysosomal repair improve renal tubular cell injury in cisplatin-induced AKI.
Renal Implications of Dysregulated Protein Homeostasis: Insights into Ubiquitin-Proteasome and Autophagy Systems.
Cardamom synergizes with cisplatin against human osteosarcoma cells by mTOR-mediated autophagy.
Interplay Between Polyphenols and Autophagy: Insights From an Aging Perspective.
Role of Testosterone Signaling in Microglia: A Potential Role for Sex-Related Differences in Alzheimer's Disease.
Secretory autophagy in neurons: more than throwing out the trash?
Somatic mosaicism and interneuron involvement in mTORopathies.
Dual-Modality Imaging Unveil Inner Mitochondrial Membrane Viscosity and Respiratory Dynamics in Mitophagy.
EPG-5 regulates tgfb/tgf-β and WNT signaling by modulating retrograde endocytic trafficking.
RHOD mediates ATG9A trafficking to promote autophagosome formation during autophagy in cancer.
Lysosomes' fallback strategies: more than just survival or death.
Sodium glucose co-transporter 2 inhibitor prevents nephrolithiasis in non-diabetes by restoring impaired autophagic flux.
Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis.
Lead Causes Lipid Droplet Accumulation by Impairing Lysosomal Function and Autophagic Flux in Testicular Sertoli Cells.
R406 and its structural analogs reduce SNCA/α-synuclein levels via autophagic degradation.
TRIM21-driven K63-linked ubiquitination of RBM38c, as a novel interactor of BECN1, contributes to DNA damage-induced autophagy.
Interplay between ALK2R206H mutant receptor and autophagy signaling regulates receptor stability and its chondrogenic functions.
Action and therapeutic targets of folliculin interacting protein 1: a novel signaling mechanism in redox regulation.
From Molecular Therapies to Lysosomal Transplantation and Targeted Drug Strategies: Present Applications, Limitations, and Future Prospects of Lysosomal Medications.
Modulation of Autophagy on Cinnamaldehyde Induced THP-1 Cell Activation.
Potential for micronuclear turnover through autophagy secretion pathway.
The Role of Mitophagy in Cardiac Metabolic Remodeling of Heart Failure: Insights of Molecular Mechanisms and Therapeutic Prospects.
Impact of diet and exercise on mitochondrial quality and mitophagy in Alzheimer's disease.
Autophagy and Respiratory Viruses: Mechanisms, Viral Exploitation, and Therapeutic Insights.
Lactoferrin influences atherosclerotic progression by modulating macrophagic AMPK/mTOR signaling-dependent autophagy.
Proteostasis and lysosomal repair deficits in transdifferentiated neurons of Alzheimer's disease.
mTOR-Mediated Autophagy Regulates Cadmium-Induced Kidney Injury via Pyroptosis.
Endophilin B1 is essential for maintaining cardiac function by regulating mitocytosis.
S-palmitoylation modulates ATG2-dependent non-vesicular lipid transport during starvation-induced autophagy.
Chlorogenic Acid Ameliorates Acetaminophen-Induced Liver Injury Through AMPK/mTOR/ULK1-Mediated Autophagy Activation.
Leucine aminopeptidase LyLAP enables lysosomal degradation of membrane proteins.
ATG16L1 WD domain and linker regulates lipid trafficking to maintain plasma membrane integrity to limit influenza virus infection.
DBeQ derivative targets vacuolar protein sorting 4 functions in cancer cells and suppresses tumor growth in mice.
Has-miR-30c-1-3p inhibits macrophage autophagy and promotes Mycobacterium tuberculosis survival by targeting ATG4B and ATG9B.
Antagonistic roles for MITF and TFE3 in melanoma plasticity.
Staphylococcus aureus reprograms CASP8 (caspase 8) signaling to evade cell death and Xenophagy.
HMBOX1 reverses autophagy mediated 5-fluorouracil resistance through promoting HACE1-induced ubiquitination and degradation of ATG5 in colorectal cancer.
Defective PINK1-dependent mitophagy is involved in high glucose-induced neurotoxicity.
Optineurin knock-out forms TDP-43 aggregates to regulate TDP-43 protein levels despite autophagic up-regulation and aberrant TDP-43 expression.
Radiotherapy modulates autophagy to reshape the tumor immune microenvironment to enhance anti-tumor immunity in esophageal cancer.
Positive feedback loop between MAPK and aquaporin 7 regulates autophagy and apoptosis induced by palmitate in RIN-m5f cells.
Mitochondria transplantation transiently rescues cerebellar neurodegeneration improving mitochondrial function and reducing mitophagy in mice.
Syntaxin 17 Translocation Mediated Mitophagy Switching Drives Hyperglycemia-Induced Vascular Injury.
DA-1241, a GPR119 agonist, ameliorates fatty liver through the upregulation of TFEB-mediated autophagy.
Lysosomal PIP3 revealed by genetically encoded lipid biosensors.
Tuberous Sclerosis Complex: New Insights into Pathogenesis and Therapeutic Breakthroughs.

Autophagy. 2025 Mar 22.

TGFB signaling induces mitophagy via PLSCR3-mediated cardiolipin externalization in conjunction with a BNIP3L/NIX-, BNIP3-, and FUNDC1-dependent mechanism.

Jiong Yan, Xin Chen, Swati Choksi, Zheng-Gang Liu.

  Selective clearance of damaged mitochondria through mitophagy is crucial for the maintenance of mitochondrial homeostasis. While mitophagy can be activated by various mitochondrial toxins, the physiologically relevant signal that triggers mitophagy is less studied. TGFB/TGFβ signaling has been linked to autophagic induction, but its specific role in mitophagy is not well understood. Here, we discovered a novel mitophagy induction paradigm stimulated by TGFB1. The mitophagic response is exclusively mediated by SMAD2, SMAD3, and SMAD4 underlying the TGFB receptor signaling. The transcriptional regulation activates genes involved in the canonical autophagic pathway which is required for the TGFB1-induced mitophagy. Moreover, TGFB1 signaling promotes mitophagic flux by upregulating PLSCR3 that externalizes cardiolipin in conjunction with the MAP1LC3/LC3/GABARAPs-interacting receptor proteins (BNIP3L/NIX, BNIP3, and FUNDC1)-dependent mechanism. Overall, our study characterized the essential components engaged in the TGFB1-induced mitophagy and demonstrated that TGFB is an important signal that induces mitophagy.

Keywords:  ATG8; BNIP3; BNIP3L/NIX; PLSCR3; TGFB/TGFβ; mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2483441
Clin Exp Nephrol. 2025 Mar 25.

Autophagic stagnation: a key mechanism in kidney disease progression linked to aging and obesity.

Takeshi Yamamoto.

  Autophagy, a critical intracellular degradation and recycling pathway mediated by lysosomes, is essential for maintaining cellular homeostasis through the quality control of proteins and organelles. Our research focused on the role of proximal tubular autophagy in the pathophysiology of aging, obesity, and diabetes. Using a novel method to monitor autophagic flux in kidney tissue, we revealed that age-associated high basal autophagy supports mitochondrial quality control and delays kidney aging. However, an impaired ability to upregulate autophagy under additional stress accelerates kidney aging. In obesity induced by a high-fat diet, lysosomal dysfunction disrupts autophagy, leading to renal lipotoxicity. Although autophagy is initially activated to repair organelle membranes and maintain proximal tubular cell integrity, this demand overwhelms lysosomes, resulting in "autophagic stagnation" characterized by phospholipid accumulation. Similar lysosomal phospholipid accumulation was observed in renal biopsies from elderly and obese patients. We identified TFEB-mediated lysosomal exocytosis as a mechanism to alleviate lipotoxicity by expelling accumulated phospholipids. Therapeutically, interventions such as the SGLT2 inhibitor empagliflozin and eicosapentaenoic acid restore lysosomal function and autophagic activity. Based on these findings, we propose a novel disease concept, "Obesity-Related Proximal Tubulopathy." This study underscores autophagic stagnation as a key driver of kidney disease progression in aging and obesity, offering insights into the pathophysiology of kidney diseases and providing a foundation for targeted therapeutic strategies.

Keywords:  Kidney aging; Lipid overload; Lysosomal dysfunction; Obesity-related proximal tubulopathy; TFEB

DOI:  https://doi.org/10.1007/s10157-025-02653-4
Nat Commun. 2025 Mar 21. 16(1): 2815

Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate.

Zhenhua Wang, Jingjing He, Yufan Yang, Yonglin He, Hongwu Qian.

The lysosome serves as an essential nutrient-sensing hub within the cell, where the mechanistic target of rapamycin complex 1 (mTORC1) is activated. Lysosomal cholesterol signaling (LYCHOS), a lysosome membrane protein, has been identified as a cholesterol sensor that couples cholesterol concentration to mTORC1 activation. However, the molecular basis is unknown. Here, we determine the cryo-electron microscopy (cryo-EM) structure of human LYCHOS at a resolution of 3.1 Å, revealing a cholesterol-like density at the interface between the permease and G-protein coupled receptor (GPCR) domains. Advanced 3D classification reveals two distinct states of LYCHOS. Comparative structural analysis between these two states demonstrated a cholesterol-related movement of GPCR domain relative to permease domain, providing structural insights into how LYCHOS senses lysosomal cholesterol levels. Additionally, we identify indoxyl sulfate (IS) as a binding ligand to the permease domain, confirmed by the LYCHOS-IS complex structure. Overall, our study provides a foundation and indicates additional directions for further investigation of the essential role of LYCHOS in the mTORC1 signaling pathway.

DOI: https://doi.org/10.1038/s41467-025-58087-9
Trends Biochem Sci. 2025 Mar 26. pii: S0968-0004(25)00049-0. [Epub ahead of print]

The emerging roles of S-acylation in autophagy.

Jia Yao, Chunyang Xie, Aimin Yang.

  Autophagy is an intracellular degradation system that delivers cytoplasmic materials to the lysosome. S-acylation, a reversible post-translational modification that attaches long-chain fatty acids to cysteine residues within proteins, has recently emerged as an important regulatory mechanism for autophagy. In this forum article, we review and discuss the emerging roles of S-acylation in autophagy.

Keywords:  ATG proteins; S-acylation; autophagy; autophagy receptor

DOI:  https://doi.org/10.1016/j.tibs.2025.02.007
Autophagy. 2025 Mar 24.

T16G12.6/IMPORTIN 13-mediated cytoplasm-to-nucleus transport of the THAP transcription factor LIN-15B controls autophagy and lysosome function in C. elegans.

Xiaoli Ma, Xiaomeng Gou, Hong Zhang.

  Transcriptional regulation of genes involved in the macroautophagy/autophagy-lysosome pathway acts as an important mechanism for controlling autophagy activity. The factors that globally regulate autophagy activity at the transcriptional level during C. elegans development remain unknown. Here we showed that the THAP domain-containing transcription factor LIN-15B modulates autophagy activity during C. elegans development. Loss of function of lin-15B suppresses the autophagy defect caused by impaired autophagosome maturation and promotes lysosome biogenesis and function. LIN-15B maintains the repressed state of genes involved in the autophagy pathway. Accordingly, loss of function of lin-15B upregulates a plethora of genes involved in autophagosome formation and maturation as well as lysosome biogenesis and function. The cytoplasm-to-nucleus translocation of LIN-15B is mediated by the T16G12.6/IMPORTIN 13/IPO-13 receptor and modulated by nutrient status. Our study uncovers that LIN-15B integrates environmental cues into transcriptional control of a network of genes involved in autophagy in C. elegans.

Keywords:  Autophagy; LIN-15B; c. elegans; lysosome; transcription

DOI:  https://doi.org/10.1080/15548627.2025.2482724
Int J Mol Sci. 2025 Mar 14. pii: 2644. [Epub ahead of print]26(6):

Methamphetamine and Methamphetamine-Induced Neuronal Exosomes Modulate the Activity of Rab7a via PTEN to Exert an Influence on the Disordered Autophagic Flux Induced in Neurons.

Hai Qiu, Manting Zhang, Minchun Li, Chuanxiang Chen, Huijun Wang, Xia Yue.

  Autophagy is a critical mechanism by which methamphetamine (METH) induces neuronal damage and neurotoxicity. Prolonged METH exposure can result in the accumulation of autophagosomes within cells. The autophagy process encompasses several essential vesicle-related biological steps, collectively referred to as the autophagic flux. However, the precise mechanisms by which METH modulates the autophagic flux and the underlying pathways remain to be elucidated. In this study, we utilized a chronic METH exposure mouse model and cell model to demonstrate that METH treatment leads to an increase in p62 and LC3B-II and the accumulation of autophagosomes in striatal neurons and SH-SY5Y cells. To assess autophagic flux, this study utilized autophagy inhibitors and inducers. The results demonstrated that the lysosomal inhibitor chloroquine exacerbated autophagosome accumulation; however, blocking autophagosome formation with 3-methyladenine did not prevent METH-induced autophagosome accumulation. Compared to the autophagy activator rapamycin, METH significantly reduced autophagosome-lysosome fusion, leading to autophagosome accumulation. Rab7a is a critical regulator of autophagosome-lysosome fusion. Although Rab7a expression was upregulated in SH-SY5Y cells and brain tissues after METH treatment, immunoprecipitation experiments revealed weakened interactions between Rab7a and the lysosomal protein RILP. Overexpression of active Rab7a (Rab7a Q67L) significantly alleviated the METH-induced upregulation of LC3-II and p62. PTEN, a key regulator of Rab7a dephosphorylation, was downregulated following METH treatment, resulting in decreased Rab7a dephosphorylation and reduced Rab7a activity, thereby contributing to autophagosome accumulation. We further investigated the role of neuronal exosomes in the autophagy process. Our results demonstrated that the miRNA expression profiles in exosomes released by METH-induced SH-SY5Y cells were significantly altered, with 122 miRNAs upregulated and 151 miRNAs downregulated. KEGG and GO enrichment analyses of these differentially expressed miRNAs and their target genes revealed significant associations with the autophagy pathway and potential regulation of PTEN expression. Our experiments confirmed that METH-induced exosomes reduced PTEN expression levels and decreased Rab7a dephosphorylation, thereby exacerbating autophagic flux impairment and autophagosome accumulation. In conclusion, our study indicated that METH and its induced neuronal exosomes downregulate PTEN expression, leading to reduced Rab7a dephosphorylation. This, in turn, hinders the fusion of autophagosomes and lysosomes, ultimately resulting in autophagic flux impairment and neuronal damage.

Keywords:  PTEN; Rab7a; autophagic flux; exosomes; methamphetamine; neuron injury; vesicular transport

DOI:  https://doi.org/10.3390/ijms26062644
CNS Neurosci Ther. 2025 Mar;31(3): e70341

Inhibition of Salt-Inducible Kinase 2 Protects Motor Neurons From Degeneration in ALS by Activating Autophagic Flux and Enhancing mTORC1 Activity.

Weiwei Liang, Chunting Zhang, Di Wang, Xiaoli Su, Xingli Tan, Yueqing Yang, Chaohua Cong, Ying Wang, Di Huo, Hongyong Wang, Shuyu Wang, Xudong Wang, Honglin Feng.

   OBJECTIVES: Autophagic impairment has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Salt-inducible kinase 2 (SIK2), a member of the AMP-activated protein kinase (AMPK) family widely expressed in the central nervous system, plays critical roles in neuronal survival, neurogenesis, and the regulation of autophagy. This study aims to investigate the effects and underlying mechanisms of SIK2 in the pathogenesis of ALS.
METHODS: In our work, we used both in vivo and in vitro models of ALS to study the effect of SIK2. Protein and RNA levels were assessed by Western blot, RT-qPCR, immunofluorescence, and immunohistochemistry. Cell viability and apoptosis were evaluated using CCK-8 assay and flow cytometry. Transmission electron microscopy was employed to examine autophagic vacuoles. Additionally, lentivirus particles carrying shRNA targeting SIK2 (sh-SIK2) were injected into the lateral ventricle of ALS mice at 60 days of age. Motor performance was evaluated by the rotarod test.
RESULTS: We observed that increased expression of SIK2 significantly contributed to the degeneration of motor neurons in both the cellular model and the hSOD1G93A transgenic mice model of ALS. SIK2 knockdown enhanced neuronal survival and restored mTORC1 activity. Furthermore, SIK2 suppression facilitated the clearance of mutant SOD1 accumulation by activating autophagic flux and enhancing lysosomal acidification. Conversely, SIK2 overexpression impaired mTORC1 activity, exacerbating autophagy dysfunction by inhibiting lysosomal function, and ultimately led to motor neuron degeneration. In vivo, SIK2 deficiency delayed disease onset and extended the lifespan of ALS mice by enhancing autophagy-mediated clearance of mutant SOD1 aggregates.
CONCLUSIONS: Our findings reveal that SIK2 regulates autophagic flux by modulating lysosomal acidification, thereby influencing the degradation of mutant SOD1 aggregates. SIK2 suppression enhances autophagy-mediated clearance of toxic protein aggregates and protects motor neurons, highlighting its potential as a therapeutic target for ALS.

Keywords:  Cu/Zn superoxide dismutase; amyotrophic lateral sclerosis; autophagy; mTORC1; salt‐inducible kinase 2

DOI:  https://doi.org/10.1111/cns.70341
Neuropharmacology. 2025 Mar 25. pii: S0028-3908(25)00139-X. [Epub ahead of print] 110433

Activated mTORC1 signaling pathway aggravates cisplatin induced oxidative damage by inhibiting autophagy in mouse cochlear hair cells.

Na-Na Xu, Yin-Chuan Wen, Jing Pan, Fan Shu, Jia-Xi Qu, Xiao-Fei Qi, Jie Tang.

  Platinum-based antitumor drugs, such as cisplatin and carboplatin, are well-known for their severe ototoxicity. The ototoxic effects of these drugs are primarily attributed to oxidative stress induced damage within cochlear hair cells (HCs), leading to cell death and subsequent irreversible hearing loss. Over the past decade, studies have demonstrated that upregulating autophagy levels in HCs can greatly alleviate the death of cochlear HCs as part of the oxidative damage induced by ototoxic drugs. However, the molecular mechanisms by which platinum-based drugs affect autophagy and ultimately lead to HCs death remain unclear. In the present study, we investigated the effects of cisplatin on the mTOR signaling pathway, a critical regulator of autophagy, in cochlear explants of mice. Our results indicated that while cisplatin enhances autophagy activity initially, it also activates mTOR Complex1 (mTORC1) within HCs. The persistent activation of mTORC1 inhibits autophagy in HCs, resulting in the accumulation of reactive oxygen species and leading to cell death. Further pharmacological experiments confirmed the protective role of rapamycin, a specific mTORC1 inhibitor, highlighting the importance of autophagy in combating cisplatin-induced ototoxicity. Our findings suggest that modulating the mTOR signaling pathway to regulate autophagy could be an effective strategy for preventing cisplatin-induced ototoxic damage.

Keywords:  Cisplatin; autophagy; hair cells; mTOR; ototoxicity; oxidative stress

DOI:  https://doi.org/10.1016/j.neuropharm.2025.110433
Sci Rep. 2025 Mar 22. 15(1): 9985

CDX1 improves nicotine induced cardiac fibroblasts activation and cardiomyocyte hypertrophy by alleviating autophagic flux impairment through modulation of LAPTM4B.

Yue-Yan Li, Fan-Liang Meng, Si-Yuan Zhou, Jia-Min Du, Wen-Jing Li, Qi-Yun Liu, Lei Wu, Meng-Meng Zhao, Yi Jin, Qun-Ye Zhang, Ying Li, Guo-Hai Su.

  Nicotine-induced impairment of autophagic flux promotes the onset of myocardial remodelling, thereby exacerbating heart failure. In this study, we investigated the role and molecular mechanisms of the transcription factor CDX1 in cardiac fibroblasts (CFs) activation and cardiomyocyte hypertrophy induced by nicotine. We found that CDX1 expression was increased in response to nicotine. However, a decrease in CDX1 further exacerbated the nicotine-induced blockade of autophagic flux, thereby aggravating CFs activation and cardiomyocyte hypertrophy. This effect was attributed to the suppression of the autophagic regulator LAPTM4B transcription by CDX1 and the subsequent activation of the mTOR pathway. In contrast, CDX1 overexpression promoted LAPTM4B expression, resulting in the opposite effect. In conclusion, our study demonstrated that CDX1/LAPTM4B axis could alleviate nicotine-induced autophagy flux impairment by inhibiting mTORC1 pathway activation, thereby alleviating CFs activation and cardiomyocyte hypertrophy, and exerting cardioprotective functions.

Keywords:  Autophagic flux; CDX1; Cardiomyocyte hypertrophy; Fibroblast activation; LAPTM4B; Nicotine

DOI:  https://doi.org/10.1038/s41598-025-94160-5
Biomolecules. 2025 Mar 18. pii: 433. [Epub ahead of print]15(3):

The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease.

Paola Zanfardino, Alessandro Amati, Mirko Perrone, Vittoria Petruzzella.

  Mitochondrial dynamics, governed by fusion and fission, are crucial for maintaining cellular homeostasis, energy production, and stress adaptation. MFN2 and OPA1, key regulators of mitochondrial fusion, play essential roles beyond their structural functions, influencing bioenergetics, intracellular signaling, and quality control mechanisms such as mitophagy. Disruptions in these processes, often caused by MFN2 or OPA1 mutations, are linked to neurodegenerative diseases like Charcot-Marie-Tooth disease type 2A (CMT2A) and autosomal dominant optic atrophy (ADOA). This review explores the molecular mechanisms underlying mitochondrial fusion, the impact of MFN2 and OPA1 dysfunction on oxidative phosphorylation and autophagy, and their role in disease progression. Additionally, we discuss the divergent cellular responses to MFN2 and OPA1 mutations, particularly in terms of proliferation, senescence, and metabolic signaling. Finally, we highlight emerging therapeutic strategies to restore mitochondrial integrity, including mTOR modulation and autophagy-targeted approaches, with potential implications for neurodegenerative disorders.

Keywords:  autophagy; mTOR signaling; mitochondria; mitochondrial dynamics; mitophagy; neurodegenerative diseases; oxidative phosphorylation; proliferation; senescence

DOI:  https://doi.org/10.3390/biom15030433
Cell Commun Signal. 2025 Mar 26. 23(1): 151

The inducible role of autophagy in cell death: emerging evidence and future perspectives.

Xiangliang Huang, Hao Yan, Zhifei Xu, Bo Yang, Peihua Luo, Qiaojun He.

   BACKGROUND: Autophagy is a lysosome-dependent degradation pathway for recycling intracellular materials and removing damaged organelles, and it is usually considered a prosurvival process in response to stress stimuli. However, increasing evidence suggests that autophagy can also drive cell death in a context-dependent manner. The bulk degradation of cell contents and the accumulation of autophagosomes are recognized as the mechanisms of cell death induced by autophagy alone. However, autophagy can also drive other forms of regulated cell death (RCD) whose mechanisms are not related to excessive autophagic vacuolization. Notably, few reviews address studies on the transformation from autophagy to RCD, and the underlying molecular mechanisms are still vague.
AIM OF REVIEW: This review aims to summarize the existing studies on autophagy-mediated RCD, to elucidate the mechanism by which autophagy initiates RCD, and to comprehensively understand the role of autophagy in determining cell fate.
KEY SCIENTIFIC CONCEPTS OF REVIEW: This review highlights the prodeath effect of autophagy, which is distinct from the generally perceived cytoprotective role, and its mechanisms are mainly associated with the selective degradation of proteins or organelles essential for cell survival and the direct involvement of the autophagy machinery in cell death. Additionally, this review highlights the need for better manipulation of autophagy activation or inhibition in different pathological contexts, depending on clinical purpose.

Keywords:  Autophagy; Autophagy machinery components; Cell death; Mammals; Selective degradation

DOI:  https://doi.org/10.1186/s12964-025-02135-w
Nat Commun. 2025 Mar 25. 16(1): 2923

The ER-phagy receptor FAM134B is targeted by Salmonella Typhimurium to promote infection.

Damián Gatica, Reham M Alsaadi, Rayan El Hamra, Boran Li, Rudolf Mueller, Makoto Miyazaki, Qiming Sun, Subash Sad, Ryan C Russell.

Macroautophagy/autophagy is a key catabolic-recycling pathway that can selectively target damaged organelles or invading pathogens for degradation. The selective autophagic degradation of the endoplasmic reticulum (hereafter referred to as ER-phagy) is a homeostatic mechanism, controlling ER size, the removal of misfolded protein aggregates, and organelle damage. ER-phagy can also be stimulated by pathogen infection. However, the link between ER-phagy and bacterial infection remains poorly understood, as are the mechanisms evolved by pathogens to escape the effects of ER-phagy. Here, we show that Salmonella enterica serovar Typhimurium inhibits ER-phagy by targeting the ER-phagy receptor FAM134B, leading to a pronounced increase in Salmonella burden after invasion. Salmonella prevents FAM134B oligomerization, which is required for efficient ER-phagy. FAM134B knock-out raises intracellular Salmonella number, while FAM134B activation reduces Salmonella burden. Additionally, we found that Salmonella targets FAM134B through the bacterial effector SopF to enhance intracellular survival through ER-phagy inhibition. Furthermore, FAM134B knock-out mice infected with Salmonella presented severe intestinal damage and increased bacterial burden. These results provide mechanistic insight into the interplay between ER-phagy and bacterial infection, highlighting a key role for FAM134B in innate immunity.

DOI: https://doi.org/10.1038/s41467-025-58035-7
Front Biosci (Landmark Ed). 2025 Mar 20. 30(3): 27091

Monitoring Autophagy in Human Aging: Key Cell Models and Insights.

Tatiana M Moreno, Jose L Nieto-Torres, Caroline Kumsta.

  Autophagy, a key cellular degradation and recycling pathway, is critical for maintaining cellular homeostasis and responding to metabolic and environmental stress. Evidence for age-related autophagic dysfunction and its implications in chronic age-related diseases including neurodegeneration is accumulating. However, as a complex, multi-step process, autophagy can be challenging to measure, particularly in humans and human aging- and disease-relevant models. This review describes the links between macroautophagy, aging, and chronic age-related diseases. We present three novel human cell models, peripheral blood mononuclear cells (PBMCs), primary dermal fibroblasts (PDFs), and induced neurons (iNs), which serve as essential tools for studying autophagy flux and assessing its potential as a biomarker for aging. Unlike traditional models, these cell models retain age- and disease-associated molecular signatures, enhancing their relevance for human studies. The development of robust tools and methodologies for measuring autophagy flux in human cell models holds promise for advancing our understanding of autophagy's role in aging and age-related diseases, ultimately facilitating the discovery of therapies to enhance health outcomes.

Keywords:  aging; autophagy; biomarkers; chronic age-related diseases; human cell models; induced neurons (iNs); peripheral blood mononuclear cells (PBMCs); primary dermal fibroblasts (PDFs)

DOI:  https://doi.org/10.31083/FBL27091
Cell Death Dis. 2025 Mar 25. 16(1): 201

ATP6AP1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy.

Zhengwei Yan, Aidi Huang, Dongwen Ma, Chenao Hong, Shengmiao Zhang, Luling He, Hai Rao, Shiwen Luo.

Autophagy is a highly conserved cellular process essential for maintaining cellular homeostasis and influencing cancer development. Lysosomal acidification and autophagosome-lysosome fusion are two important steps of autophagy degradation that are tightly regulated. Although many key proteins that regulate these two events have been identified, the effector proteins that co-regulate both steps remain to be explored. ATP6AP1, an accessory subunit of V-ATPase, plays a critical role in the assembly and regulation of V-ATPase. However, the function of ATP6AP1 in autophagy remains unknown, and the role of ATP6AP1 in cancer is still poorly understood. In this study, we found that ATP6AP1 is overexpressed in luminal breast cancer tissues and promotes the proliferation and tamoxifen resistance of luminal breast cancer cells both in vitro and in vivo. We also observed that high ATP6AP1 expression correlates with poor overall patient survival. Our research further revealed that ATP6AP1 enhances tamoxifen resistance by activating autophagy. Mechanistically, ATP6AP1 promotes autophagy by regulating both lysosomal acidification and autophagosome-lysosome fusion. Remarkably, ATP6AP1 induces lysosomal acidification through the regulation of V-ATPase assembly and facilitates autophagosome-lysosome fusion by enhancing the interaction between Rab7 and the HOPS complex. Together, our studies identify ATP6AP1 as a crucial regulator of autophagy, potentially serving as a valuable prognostic marker or therapeutic target in human luminal breast cancer.

DOI: https://doi.org/10.1038/s41419-025-07534-y
Sci Adv. 2025 Mar 28. 11(13): eadt3311

Mycobacterium tuberculosis phagosome Ca2+ leakage triggers multimembrane ATG8/LC3 lipidation to restrict damage in human macrophages.

Di Chen, Antony Fearns, Maximiliano G Gutierrez.

The role of canonical autophagy in controlling Mycobacterium tuberculosis (Mtb), referred to as xenophagy, is understood to involve targeting Mtb to autophagosomes, which subsequently fuse with lysosomes for degradation. Here, we found that Ca2+ leakage after Mtb phagosome damage in human macrophages is the signal that triggers autophagy-related protein 8/microtubule-associated proteins 1A/1B light chain 3 (ATG8/LC3) lipidation. Unexpectedly, ATG8/LC3 lipidation did not target Mtb to lysosomes, excluding the canonical xenophagy. Upon Mtb phagosome damage, the Ca2+ leakage-dependent ATG8/LC3 lipidation occurred on multiple membranes instead of single or double membranes excluding the noncanonical autophagy pathways. Mechanistically, Ca2+ leakage from the phagosome triggered the recruitment of the V-ATPase-ATG16L1 complex independently of FIP200, ATG13, and proton gradient disruption. Furthermore, the Ca2+ leakage-dependent ATG8/LC3 lipidation limited Mtb phagosome damage and restricted Mtb replication. Together, we uncovered Ca2+ leakage as the key signal that triggers ATG8/LC3 lipidation on multiple membranes to mitigate Mtb phagosome damage.

DOI: https://doi.org/10.1126/sciadv.adt3311
J Neurochem. 2025 Mar;169(3): e70048

Hippocampal Inhibitory Interneuron-Specific DREADDs Treatment Alters mTORC1-4E-BP Signaling and Impairs Memory Formation.

Ziying Huang, Niaz Mahmood, Jean-Claude Lacaille, Shane Wiebe, Nahum Sonenberg.

  Control of protein synthesis via the mechanistic target of rapamycin complex 1 (mTORC1) is essential for learning and memory. However, the cell-type-specific and spatiotemporal regulation of this pathway during memory formation is not well understood. In this study, we expressed artificial human muscarinic M3 [hM3D(Gq)] or M4 [hM4D(Gi)] designer receptors exclusively activated by designer drugs (DREADDs) in hippocampal CA1 excitatory or inhibitory neurons of adult mice. We studied the impact of clozapine-N-oxide (CNO), a synthetic DREADDs agonist, on the mTORC1 pathway and long-term memory. hM3D(Gq) and hM4D(Gi) activate or inactivate, respectively, mTORC1 signaling in hippocampal interneurons, as indicated by the phosphorylation of its targets, eukaryotic initiation factor 4E-binding proteins (4E-BP1/2) and ribosomal protein S6 (S6). Activation of either hM3D(Gq) or hM4D(Gi) in mice immediately after training in memory tasks impaired long-term memory formation in inhibitory, but not in excitatory neurons. The findings underscore the importance of activity-dependent mTORC1-4E-BP1/2 signaling in hippocampal inhibitory interneurons for memory formation.

Keywords:  4E‐BP; clozapine‐N‐oxide; hippocampus; interneurons; mTORC1; memory

DOI:  https://doi.org/10.1111/jnc.70048
MedComm (2020). 2025 Apr;6(4): e70144

(-)-Epicatechin Rescues Memory Deficits by Activation of Autophagy in a Mouse Model of Tauopathies.

Yanqing Wu, Ting Li, Xingjun Jiang, Jianmin Ling, Zaihua Zhao, Jiahui Zhu, Chongyang Chen, Qian Liu, Xifei Yang, Xuefeng Shen, Rong Ma, Gang Li, Gongping Liu.

  In tauopathies, defects in autophagy-lysosomal protein degradation are thought to contribute to the abnormal accumulation of aggregated tau. Recent studies have shown that (-)-Epicatechin (Epi), a dietary flavonoid belonging to the flavan-3-ol subgroup, improves blood flow, modulates metabolic profiles, and prevents oxidative damage. However, less research has explored the effects of Epi on tauopathies. Here, we found that Epi rescued cognitive deficits in P301S tau transgenic mice, a model exhibiting characteristics of tauopathies like frontotemporal dementia and Alzheimer's disease, and attenuated tau pathology through autophagy activation. Proteomic and biochemical analyses revealed that P301S mice exhibit deficits in autophagosome formation via modulating mTOR, consequently inhibiting autophagy. Epi inhibited the mTOR signaling pathway to promote autophagosome formation, which is essential for the clearance of tau aggregation. By using chloroquine (CQ) to inhibit autophagy in vivo, we further confirmed that Epi induced tau degradation via the autophagy pathway. Lastly, Epi administration was also found to improve cognition by reversing spine decrease and neuron loss, as well as attenuating neuroinflammation. Our findings suggest that Epi promoted tau clearance by activating autophagy, indicating its potential as a promising therapeutic candidate for tauopathies.

Keywords:  (−)‐Epicatechin; FTDP; autophagy; memory deficits; tauopathies

DOI:  https://doi.org/10.1002/mco2.70144
Autophagy. 2025 Mar 28.

ESCRT iii-mediated lysosomal repair improve renal tubular cell injury in cisplatin-induced AKI.

Zhangyu Tian, Yiming Wu, Bin Yi, Ling Li, Yan Liu, Hao Zhang, Aimei Li.

  The chemotherapeutic agent cisplatin is widely utilized for the treatment of various solid tumors. However, its clinical utility is limited by nephrotoxicity. Although numerous studies have demonstrated the potential of enhancing macroautophagy/autophagy in alleviating cisplatin-induced acute kidney injury (AKI), the dynamics of the autophagic process during renal tubular injury remain to be elucidated. In our investigation, we observed that cisplatin treatment leads to increased expression of LC3-II, GABARAPL1, SQSTM1/p62 and NBR1 in mouse renal tubular epithelial cells and BUMPT cells. Moreover, ultrastructurally, there is extensive accumulation of autophagic vacuoles in AKI mice. These findings imply that cisplatin-induced AKI results in impaired autophagic flow within renal tubular cells. Furthermore, LGALS3 (galectin 3) was found to be enriched in lysosomes after cisplatin treatment, revealing a close association between autophagy dysfunction and impaired lysosomal membrane integrity. Given the damaging contents of lysosomes, lysosomal membrane permeabilization must be rapidly resolved. Our findings showed that ESCRT III subunit CHMP4A-mediated lysosomal membrane repair significantly ameliorates autophagic defects and protects against lysosomal damage-induced cell death in a cisplatin-induced AKI model. In conclusion, our study indicates that ESCRT III-mediated lysosomal repair can relieve cisplatin-induced cell apoptosis and restore normal autophagy function in renal tubular epithelial cells. This mechanism plays a protective role against cisplatin-induced AKI.

Keywords:  Apoptosis; Cisplatin-induced AKI; ESCRT III; autophagy; lysosomal damage; lysosomal repair

DOI:  https://doi.org/10.1080/15548627.2025.2483598
Biomolecules. 2025 Feb 28. pii: 349. [Epub ahead of print]15(3):

Renal Implications of Dysregulated Protein Homeostasis: Insights into Ubiquitin-Proteasome and Autophagy Systems.

Charlotte Delrue, Marijn M Speeckaert.

  The ubiquitin-proteasome system (UPS) and autophagy maintain protein homeostasis, which is critical to cellular function and survival. The dysregulation of these pathways has been recognized as a hallmark of acute kidney injury and chronic kidney disease. This review elucidates the role of the UPS and autophagy in kidney disease, namely through inflammation, oxidative stress, fibrosis and apoptosis. The pathways of NF-κB, TGF-β and mitochondrial failure result in glomerular injury and tubulointerstitial fibrosis due to impaired proteostasis in podocytes and tubular epithelial cells. Recent studies have revealed a connection between the autophagic process and the UPS, wherein compensatory mechanisms aim to spike down proteotoxic stress but eventually seem inadequate in cases of chronic derangement. Low-dose pharmacological inhibitors, autophagy modulators, and new gene and nanotechnology-based treatments may all help to restore the protein balance and reduce kidney injury. A more thorough understanding of these pathways is needed to develop kidney-protective and disease-modifying therapeutic interventions.

Keywords:  autophagy; chronic kidney disease; protein homeostasis; ubiquitin–proteasome system

DOI:  https://doi.org/10.3390/biom15030349
Cancer Gene Ther. 2025 Mar 26.

Cardamom synergizes with cisplatin against human osteosarcoma cells by mTOR-mediated autophagy.

Sheng Li, Ziyun Li, Jiayu Wang, Xueqian Han, Lulu Zhang.

Cisplatin (DDP), a frontline chemotherapeutic agent in osteosarcoma (OS) treatment, is frequently paired with other compounds to enhance its therapeutic potency. Cardamom (CAR), a natural flavonoid, exhibits significant inhibitory effects on human OS cells while minimizing toxic side effects. In this study, we combined CAR and DDP to treat OS, revealing that the DDP/CAR combination synergistically inhibits the growth of human OS cells in vitro and in vivo. Network pharmacological analysis indicated that mammalian target of rapamycin (mTOR) may be an important cross-target for DDP/CAR combination. Notably, this combined treatment significantly reduced mTOR phosphorylation and elevated autophagy levels within OS cells. At the mechanistic level, the DDP/CAR regimen enhanced apoptosis and compromised the viability of OS cells by triggering autophagy. This impact was attenuated by the use of the mTOR activator MHY and the autophagy inhibitor hydroxychloroquine (HCQ). Furthermore, in DDP-resistant cell lines, CAR was able to mitigate DDP resistance by bolstering autophagy levels. In general, our results suggest that CAR bolstering autophagy levels DDP against OS cells through the induction of mTOR-mediated autophagy.

DOI: https://doi.org/10.1038/s41417-025-00894-9
Front Biosci (Landmark Ed). 2025 Mar 19. 30(3): 25728

Interplay Between Polyphenols and Autophagy: Insights From an Aging Perspective.

Alejandro Ponce-Mora, Nicolle Andrea Salazar, Alicia Domenech-Bendaña, Antonella Locascio, Eloy Bejarano, Lucia Gimeno-Mallench.

  The relationship between polyphenols and autophagy, particularly in the context of aging, presents a promising avenue for therapeutic interventions in age-related diseases. A decline in autophagy is associated with aging-related affections, and an increasing number of studies suggest that this enhancement is linked to cellular resilience and longevity. This review delves into the multifaceted roles of autophagy in cellular homeostasis and the potential of polyphenols to modulate autophagic pathways. We revised the most updated literature regarding the modulatory effects of polyphenols on autophagy in cardiovascular, liver, and kidney diseases, highlighting their therapeutic potential. We highlight the role of polyphenols as modulators of autophagy to combat age-related diseases, thus contributing to improving the quality of life in aging populations. A better understanding of the interplay of autophagy between autophagy and polyphenols will help pave the way for future research and clinical applications in the field of longevity medicine.

Keywords:  aging; autophagy; polyphenols

DOI:  https://doi.org/10.31083/FBL25728
Adv Sci (Weinh). 2025 Mar 24. e2413375

Role of Testosterone Signaling in Microglia: A Potential Role for Sex-Related Differences in Alzheimer's Disease.

Haiyan Du, Akiko Mizokami, Junjun Ni, Simeng Zhang, Yosuke Yamawaki, Tomomi Sano, Eijiro Jimi, Isei Tanida, Takashi Kanematsu.

  Alzheimer's disease (AD) is less prevalent in men than in women, although mechanisms remain unclear. Microglia degrade aggregated amyloid β (Aβ) through the lysosomal system, including autophagy. G protein-coupled receptor family C group 6 member A (GPRC6A), predominantly expressed in mouse microglial MG6 cells, is a primary mediator of testosterone signaling. This study examines testosterone's role in modulating Aβ-induced autophagy in microglia. Testosterone promotes Aβ-induced autophagy leading to Aβ clearance in MG6 cells by suppressing extracellular signal-regulated kinase (ERK) phosphorylation and subsequently inhibiting mammalian target of rapamycin (mTOR) activation, which is abrogated by shRNA knockdown of GPRC6A. In in vivo experiments with male 5xFAD AD model mice, Aβ clearance activity is associated with autophagy in microglia and is reduced by orchiectomy, but restored by testosterone supplementation. ERK phosphorylation in the brains of male AD model mice is upregulated by orchiectomy. Therefore, testosterone is involved in autophagy-mediated Aβ clearance in microglia. Aβ accumulation in human brain samples from patients with AD is significantly lower in men than in women, with less pronounced colocalization of Aβ with p62 aggregates, suggesting enhanced autophagic activity in men. In conclusion, testosterone enhances Aβ-induced autophagy in microglia, possibly contributing to lower susceptibility to AD in men.

Keywords:  Alzheimer's disease; autophagy; microglia; sex‐related differences; testosterone

DOI:  https://doi.org/10.1002/advs.202413375
Neural Regen Res. 2025 Mar 25.

Secretory autophagy in neurons: more than throwing out the trash?

Alexander Veh, Patrick Lüningschrör.

DOI: https://doi.org/10.4103/NRR.NRR-D-24-01514
Trends Neurosci. 2025 Mar 21. pii: S0166-2236(25)00040-2. [Epub ahead of print]

Somatic mosaicism and interneuron involvement in mTORopathies.

Lilian G Jerow, Darcy A Krueger, Christina Gross, Steve C Danzer.

  Somatic mutations in genes regulating mechanistic target of rapamycin (mTOR) pathway signaling can cause epilepsy, autism, and cognitive dysfunction. Research has predominantly focused on mTOR regulation of excitatory neurons in these conditions; however, dysregulated mTOR signaling among interneurons may also be critical. In this review, we discuss clinical evidence for interneuron involvement, and potential mechanisms, known and hypothetical, by which interneurons might come to directly harbor pathogenic mutations. To understand how mTOR hyperactive interneurons might drive dysfunction, we review studies in which mTOR signaling has been selectively disrupted among interneurons and interneuron progenitors in mouse model systems. Complex cellular mosaicism and dual roles for mTOR (hyper)activation in mediating disease pathogenesis and homeostatic responses raise challenging questions for effective treatment of these disorders.

Keywords:  epilepsy; focal cortical dysplasia; parvalbumin; somatostatin; tuberous sclerosis complex

DOI:  https://doi.org/10.1016/j.tins.2025.02.009
Anal Chem. 2025 Mar 27.

Dual-Modality Imaging Unveil Inner Mitochondrial Membrane Viscosity and Respiratory Dynamics in Mitophagy.

Fei Peng, Xiangnan Ai, Bin Hao, Xiaoyu Bu, Zixuan Zhao, Linshuai Yang, Baoxiang Gao.

Mitophagy is a vital lysosome-dependent process that maintains mitochondrial integrity and cellular homeostasis, where respiration and inner mitochondrial membrane (IMM) viscosity play key roles. Despite its critical importance, achieving a high-resolution and dynamic visualization of respiration and IMM viscosity during mitophagy remains a significant challenge. In this study, we designed two innovative fluorescent probes: SiR-C8, a viscosity-sensitive rotor-type probe based on silicon-rhodamine, specifically targeting the IMM, and OR-ATP, a rhodamine-derived probe utilizing an intramolecular spirolactam structure to respond to mitochondrial ATP levels. Leveraging fluorescence intensity and lifetime dual-modality imaging, we successfully enabled the high-resolution, real-time monitoring of lysosome-dependent mitophagy. Remarkably, our results unveiled a progressive increase in IMM viscosity alongside a significant attenuation in mitochondrial respiration during mitophagy induced by starvation, carbonyl cyanide, m-chlorophenyl hydrazone (CCCP), and Oligomycin. Significantly, utilizing structured illumination microscopy super-resolution imaging, we have uncovered a novel mitochondrial quality control mechanism by which lysosomes selectively engulf locally damaged mitochondrial regions. This discovery provides novel insights into the intricate processes governing mitophagy and introduces an innovative platform for studying mitochondrial dynamics, dysfunction, and their implications for cellular homeostasis and pathology.

DOI: https://doi.org/10.1021/acs.analchem.5c00464
Autophagy. 2025 Mar 28.

EPG-5 regulates tgfb/tgf-β and WNT signaling by modulating retrograde endocytic trafficking.

Chongzhen Yuan, Huachuan Dong, Chunyan Wu, Jinyang Liu, Zheng Wang, Xingwei Wang, Haiyan Ren, Zhaoyu Wang, Qun Lu.

  The Vici syndrome protein EPG5 acts as a tethering factor determining the fusion specificity of autophagosomes with late endosomes/lysosomes. Here we demonstrated that during C. elegans development, EPG-5 modulates SMA and MAB TGFB/TGF-β signaling in controlling body size and also WNT signaling in regulating cell migration. EPG-5 is required for retrograde trafficking of the TGFB receptor SMA-6 and WLS/Wntless homolog MIG-14. In epg-5 mutants, SMA-6 and MIG-14 are trapped within hybrid endosomal structures, which colocalize with SNX-1- and SNX-3-labeled vesicles, respectively. Basolateral recycling processes of transmembrane cargos H.s.TFR/hTfR and H.s.IL2RA/hTAC are also defective in epg-5 mutants. Depletion of EPG-5 causes defective RAB-5 and RAB-7, and RAB-5 and RAB-10 conversion, leading to the formation of these hybrid vesicles. The defects in endocytic trafficking and autophagy in epg-5 mutants are ameliorated by knocking down components of the HOPS complex. Our study demonstrates the intersection between the autophagy pathway and the endocytic pathway, providing insights into the pathogenesis of amyotrophic lateral sclerosis (ALS) and Vici syndrome.

Keywords:  Autophagy; TGFB; WNT; epg-5; retrograde recycling

DOI:  https://doi.org/10.1080/15548627.2025.2485420
Autophagy. 2025 Mar 26.

RHOD mediates ATG9A trafficking to promote autophagosome formation during autophagy in cancer.

Sijia Wang, Jing Ren, Jinghan Chi, Yifei Guan, Ran Zheng, Juan Wang, Xinhui Liu, Hua Huang.

  ATG9A is a transmembrane protein essential for macroautophagy/autophagy that drives autophagosome formation by delivering essential proteins and lipids to the phagophore through vesicle trafficking. Here, we demonstrate that the atypical Rho GTPase RHOD is required for ATG9A trafficking and stimulates autophagosome formation. Upon starvation, RHOD interacted with ATG9A and accompanied ATG9A trafficking from the Golgi toward phagophores. In addition, starvation-induced high levels of RHOD resulted in Golgi fragmentation to further promote ATG9A vesicle export from the trans-Golgi network to the peripheral region. Loss of RHOD suppressed ATG9A trafficking and reduced the distribution of ATG9A on the phagophore. Moreover, WHAMM (WASP homolog associated with actin, golgi membranes and microtubules) forms a complex with RHOD and participates in this process in a RHOD-dependent manner. Importantly, RHOD mutants, which lack the exon II-containing effector region motif that is required for ATG9A binding or lack the CAAX box that is responsible for membrane targeting, fail to stimulate ATG9A trafficking and autophagosome formation. Furthermore, RHOD plays a distinct suppressor role in tumor development, partly associated with its regulatory effect on autophagy. These findings reveal the important roles of RHOD in autophagy and tumor development.

Keywords:  ATG9A; RHOD; WHAMM; autophagy; lung cancer; vesicle trafficking

DOI:  https://doi.org/10.1080/15548627.2025.2484604
Front Cell Dev Biol. 2025 ;13 1559504

Lysosomes' fallback strategies: more than just survival or death.

Quan Wang, Ruolin Wang, Haihui Hu, Xiaoqing Huo, Fulong Wang.

  Lysosomes are heterogeneous, acidic organelles whose proper functionality is critically dependent on maintaining the integrity of their membranes and the acidity within their lumen. When subjected to stress, the lysosomal membrane can become permeabilized, posing a significant risk to the organelle's survival and necessitating prompt repair. Although numerous mechanisms for lysosomal repair have been identified in recent years, the progression of lysosome-related diseases is more closely linked to the organelle's alternative strategies when repair mechanisms fail, particularly in the contexts of aging and pathogen infection. This review explores lysosomal responses to damage, including the secretion of lysosomal contents and the interactions with lysosome-associated organelles in the endolysosomal system. Furthermore, it examines the role of organelles outside this system, such as the endoplasmic reticulum (ER) and Golgi apparatus, as auxiliary organelles of the endolysosomal system. These alternative strategies are crucial to understanding disease progression. For instance, the secretion and spread of misfolded proteins play key roles in neurodegenerative disease advancement, while pathogen escape via lysosomal secretion and lysosomotropic drug expulsion underlie cancer treatment resistance. Reexamining these lysosomal fallback strategies could provide new perspectives on lysosomal biology and their contribution to disease progression.

Keywords:  autophagy; endoplasmic reticulum; exosome; golgi apparatus; lysosomal damage; secretion

DOI:  https://doi.org/10.3389/fcell.2025.1559504
EBioMedicine. 2025 Mar 25. pii: S2352-3964(25)00112-4. [Epub ahead of print]114 105668

Sodium glucose co-transporter 2 inhibitor prevents nephrolithiasis in non-diabetes by restoring impaired autophagic flux.

Chan-Jung Liu, Kaun-Ta Ho, Ho-Shiang Huang, Ze-Hong Lu, Miyuki Hsing-Chun Hsieh, Yu-Shan Chang, Wei-Hsuan Wang, Edward Chia-Cheng Lai, Yau-Sheng Tsai.

   BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) offer significant cardiovascular and kidney protection, independent of diabetes mellitus (DM). Recent cohort studies also suggest that SGLT2i can decrease the risk of nephrolithiasis in patients with DM. We aimed to use both animal models and human data to investigate whether SGLT2i can prevent nephrolithiasis and explored autophagy as a possible mechanism.
METHODS: We utilised SGLT2i, dapagliflozin (DAPA), on a glyoxylate (GOX)-induced calcium oxalate (CaOx) nephrolithiasis non-DM mouse model to test whether SGLT2i inhibited CaOx stone formation through modulating autophagy. Moreover, the clinical data retrieved from the National Health Insurance Research Database was analysed to confirm the findings from animal models.
FINDINGS: DAPA increased urine citrate, magnesium, pH, and decreased oxalate, effectively inhibiting CaOx stones in GOX mice. While autophagy was increased in the kidneys of GOX mice, as demonstrated by upregulated AMP-activated protein kinase (AMPK) and increased LC3B conversion; impaired autophagic flux was indicated by p62 accumulation. DAPA improved autophagy by downregulating mammalian target of rapamycin (mTOR), AMPK, and restoring autophagic flux. Rapamycin co-treatment preserved DAPA's nephrolithiasis inhibition, while hydroxychloroquine (HCQ) co-treatment abolished it. Finally, cohort data confirmed that SGLT2i reduced nephrolithiasis risk, but this protective effect disappeared if HCQ had been used within the prior year, suggesting that HCQ may compromise SGLT2i's protection against nephrolithiasis.
INTERPRETATION: SGLT2i, DAPA, inhibits nephrolithiasis by restoring impaired autophagic flux, and co-administration with autophagy inhibitor, HCQ, compromises SGLT2i's protection.
FUNDING: This research was funded by grants from the National Science and Technology Council, Taiwan (110-2314-B-006-023, 110-2320-B-006-017MY3, and 112-2314-B-006-058) and the research grants (NCKUH-11202005, -11210020) from the National Cheng Kung University Hospital, Tainan, Taiwan.

Keywords:  Autophagy; Cohort studies; Dapagliflozin; Lysosome; Nephrolithiasis; Sodium–glucose cotransporter 2 inhibitors

DOI:  https://doi.org/10.1016/j.ebiom.2025.105668
Nat Commun. 2025 Mar 24. 16(1): 2749

Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis.

Alexandra E Preston, Joe N Frost, Megan R Teh, Mohsin Badat, Andrew E Armitage, Ruggiero Norfo, Sarah K Wideman, Muhammad Hanifi, Natasha White, Noémi Ba Roy, Christian Babbs, Bart Ghesquiere, James Davies, Andrew Jm Howden, Linda V Sinclair, Jim R Hughes, Mira Kassouf, Rob Beagrie, Douglas R Higgs, Hal Drakesmith.

Red blood cell development from erythroid progenitors requires profound reshaping of metabolism and gene expression. How these transcriptional and metabolic alterations are coupled is unclear. Nprl3 (an inhibitor of mTORC1) has remained in synteny with the α-globin genes for >500 million years, and harbours most of the a-globin enhancers. However, whether Nprl3 serves an erythroid role is unknown. We found that while haematopoietic progenitors require basal Nprl3 expression, erythroid Nprl3 expression is further boosted by the α-globin enhancers. This lineage-specific upregulation is required for sufficient erythropoiesis. Loss of Nprl3 affects erythroblast metabolism via elevating mTORC1 signalling, suppressing autophagy and disrupting glycolysis. Broadly consistent with these murine findings, human NPRL3-knockout erythroid progenitors produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Therefore, we propose that the anciently conserved linkage of NprI3, α-globin and their associated enhancers has coupled metabolic and developmental control of erythropoiesis.

DOI: https://doi.org/10.1038/s41467-025-57683-z
Toxics. 2025 Feb 28. pii: 175. [Epub ahead of print]13(3):

Lead Causes Lipid Droplet Accumulation by Impairing Lysosomal Function and Autophagic Flux in Testicular Sertoli Cells.

Chengwei Guo, Lingqiao Wang, Ke Cui, Guowei Zhang, Yao Tan, Weiyan Chen, Yiqi Wang, Jijun Liu, Wenbin Liu, Guanghui Zhang, Ziyuan Zhou.

  Lead (Pb) is one of the most common environmental pollutants that negatively impacts male reproductive health. Thus far, the underlying molecular mechanisms of Pb-induced reproductive toxicity are still not well understood. In this study, 64 male ICR mice were given drinking water with Pb (0, 100, 200, and 300 mg/L) for 90 days. We found that exposure to 300 mg/L Pb resulted in reduced sperm quality and elevated autophagy-related protein levels in the mouse testes. Our findings indicate that the Pb hindered the autophagic clearance by impairing the lysosomes' function and then obstructing the fusion of lysosomes and autophagosomes. The autophagy cycle obstruction prevented the lipid droplets from breakdown and led to their accumulation in the Sertoli cells. In turn, the ccytotoxic effects that resulted from the interruption of the autophagy maturation stage, instead of the elongation phase, could be alleviated by either Chloroquine or Bafilomycin A1. Furthermore, exposure to 400 μM Pb initiated the TFE3 nuclear translocation and caused the increased expression of its target genes. Then, the knockdown of TFE3 reduced the formation of the autophagosome. In addition, the use of the antioxidant NAC notably enhanced the autophagic activity and reduced the occurrence of lipid droplets in the Sertoli cells. This study demonstrated that Pb disrupted the autophagic flow, which caused lipid droplet accumulation in the TM4 cells. Consequently, focusing on the maturation stage of autophagy might offer a potential therapeutic approach to alleviate male reproductive toxicity caused by Pb exposure.

Keywords:  ROS; TFE3; autophagy; lead; male reproduction

DOI:  https://doi.org/10.3390/toxics13030175
Autophagy. 2025 Mar 26.

R406 and its structural analogs reduce SNCA/α-synuclein levels via autophagic degradation.

Chao Zhong, Xiaoge Gao, Qi Chen, Bowen Guan, Wanli Wu, Zhiqiang Ma, Mengdan Tao, Xihuan Liu, Yu Ding, Yiyan Fei, Yan Liu, Boxun Lu, Zhaoyang Li.

  The presence of neuronal Lewy bodies mainly composed of SNCA/α-synuclein aggregations is a pathological feature of Parkinson disease (PD), whereas reducing SNCA protein levels may slow the progression of this disease. We hypothesized that compounds enhancing SNCA's interaction with MAP1LC3/LC3 May increase its macroautophagic/autophagic degradation. Here, we conducted small molecule microarray (SMM)-based screening to identify such compounds and revealed that the compound R406 could decrease SNCA protein levels in an autophagy-dependent manner. We further validated the proposed mechanism, in which knockdown of essential gene ATG5 for autophagy formation and using the autophagy inhibitor chloroquine (CQ) blocked the effect of R406. Additionally, R406 also reduced the levels of phosphorylated serine 129 of SNCA (p-S129-SNCA) in SNCA preformed fibrils (PFFs)-induced cellular models and rescued neuron degeneration.

Keywords:  Autophagic degradation; Snca/synuclein alpha; parkinson disease; small molecule compounds

DOI:  https://doi.org/10.1080/15548627.2025.2483886
Cell Death Differ. 2025 Mar 25.

TRIM21-driven K63-linked ubiquitination of RBM38c, as a novel interactor of BECN1, contributes to DNA damage-induced autophagy.

Lishenglan Xia, Yusheng Xing, Xinjia Ye, Yuanshun Wu, Ying Yang, Ziyi Yin, Anni Wang, Jian Chen, Min Zhang.

Autophagy is essential in DNA damage response by limiting damage, but its responsive activation remains unclear. RBM38 (RBM38a), an RNA-binding protein, regulates mRNA metabolism and plays a key role in controlling cell cycle progression, senescence, and cancer. In this study, we uncovered a novel primate-specific isoform, RBM38c, with 32 extra amino acids from exon 2, which imparts a distinct capacity to promote autophagy upon DNA damage. TP53 increases RBM38c expression upon DNA damage, while TRIM21 facilitates its K63-linked ubiquitination at lysine (K) 35. Activated RBM38c enhances its interaction with BECN1, promoting the formation of the ATG14-containing PtdIns3K-C1 complex and thus autophagy initiation. A K35R mutation or TRIM21 deficiency impairs RBM38c ubiquitination, preventing autophagy activation upon DNA damage. Moreover, RBM38c-driven autophagy protects cells from DNA damage-induced apoptosis and promotes survival, with this beneficial effect susceptible to suppression by the autophagy inhibitor 3-methyladenine. Consequently, depleting RBM38c enhances the efficacy of DNA-damaging drugs by impairing autophagy and increasing DNA damage. Clinical lung cancer samples show a positive correlation between RBM38c expression and LC3 expression, and this correlation is linked to chemotherapy resistance. Together, our study reveals a novel mechanism for DNA damage-induced autophagy, involving K63-linked ubiquitination of RBM38c as a critical interactor with BECN1.

DOI: https://doi.org/10.1038/s41418-025-01480-0
Cell Death Discov. 2025 Mar 22. 11(1): 117

Interplay between ALK2R206H mutant receptor and autophagy signaling regulates receptor stability and its chondrogenic functions.

Laura Coculo, Marius Wits, Irene Mariani, Giulia Fianco, Serena Cappato, Renata Bocciardi, Nicoletta Pedemonte, Elisabetta Volpe, Serena Ciolfi, Rosario Luigi Sessa, Serena Rinaldo, Francesca Cutruzzolà, Daniela Trisciuoglio, Marie-Josè Goumans, Gonzalo Sanchez-Duffhues, Venturina Stagni.

Heterozygous mutations in the Bone morphogenetic protein (BMP) type I receptor ACVR1, encoding activin-like kinase 2 (ALK2), underlie all cases of the rare genetic musculoskeletal disorder Fibrodysplasia Ossificans Progressiva (FOP). The most commonly found mutant ALK2 p.R206H receptor variant exhibits loss of auto inhibition of BMP signaling and can be activated by Activins, while wild-type receptors remain unresponsive. Consequently, the downstream chondrogenic signaling is enhanced, thus driving heterotopic ossification within soft connective tissues. Despite several investigational treatments being evaluated in clinical trials, no cure for FOP exists today. The cellular and molecular mechanisms underlying disease progression are still being deciphered. In this study, we show a close interplay between the mutant ALK2R206H receptor signaling and dysregulation of the autophagic flux triggered by hypoxia. Mechanistically, reduced autophagic flux correlates with increased stability of ALK2R206H, resulting in sustained signaling. Of note, we demonstrated that Rapamycin, under clinical investigation as a treatment for FOP, inhibits chondrogenic differentiation in an autophagy-dependent manner. Consistently, other pharmacological autophagy inducers, like Spermidine, can reduce ALK2R206H driven chondrogenic differentiation in vitro. These results were verified in FOP patient-derived cells. In conclusion, this study shows that aberrant autophagic flux mediates sustained ALK2R206H signaling, introducing a novel druggable target in FOP by reactivating autophagy.

DOI: https://doi.org/10.1038/s41420-025-02393-0
Front Cell Dev Biol. 2025 ;13 1523489

Action and therapeutic targets of folliculin interacting protein 1: a novel signaling mechanism in redox regulation.

Qingzhi Ran, Aoshuang Li, Bo Yao, Chunrong Xiang, Chunyi Qu, Yongkang Zhang, Xuanhui He, Hengwen Chen.

  Rapid activation of adenosine monophosphate-activated protein kinase (AMPK) induces phosphorylation of mitochondrial-associated proteins, a process by which phosphate groups are added to regulate mitochondrial function, thereby modulating mitochondrial energy metabolism, triggering an acute metabolic response, and sustaining metabolic adaptation through transcriptional regulation. AMPK directly phosphorylates folliculin interacting protein 1 (FNIP1), leading to the nuclear translocation of transcription factor EB (TFEB) in response to mitochondrial functions. While mitochondrial function is tightly linked to finely-tuned energy-sensing mobility, FNIP1 plays critical roles in glucose transport and sensing, mitochondrial autophagy, cellular stress response, and muscle fiber contraction. Consequently, FNIP1 emerges as a promising novel target for addressing aberrant mitochondrial energy metabolism. Recent evidence indicates that FNIP1 is implicated in mitochondrial biology through various pathways, including AMPK, mTOR, and ubiquitination, which regulate mitochondrial autophagy, oxidative stress responses, and skeletal muscle contraction. Nonetheless, there is a dearth of literature discussing the physiological mechanism of action of FNIP1 as a novel therapeutic target. This review outlines how FNIP1 regulates metabolic-related signaling pathways and enzyme activities, such as modulating mitochondrial energy metabolism, catalytic activity of metabolic enzymes, and the homeostasis of metabolic products, thereby controlling cellular function and fate in different contexts. Our focus will be on elucidating how these metabolite-mediated signaling pathways regulate physiological processes and inflammatory diseases.

Keywords:  autophagy; folliculin interacting protein 1; glucose sensing; intracellular metabolism; mitochondria; muscle fiber contraction; reductive stress

DOI:  https://doi.org/10.3389/fcell.2025.1523489
Biomolecules. 2025 Feb 24. pii: 327. [Epub ahead of print]15(3):

From Molecular Therapies to Lysosomal Transplantation and Targeted Drug Strategies: Present Applications, Limitations, and Future Prospects of Lysosomal Medications.

Adel A Alhowyan, Gamaleldin I Harisa.

  Lysosomes are essential intracellular organelles involved in plentiful cellular processes such as cell signaling, metabolism, growth, apoptosis, autophagy, protein processing, and maintaining cellular homeostasis. Their dysfunction is linked to various diseases, including lysosomal storage disorders, inflammation, cancer, cardiovascular diseases, neurodegenerative conditions, and aging. This review focuses on current and emerging therapies for lysosomal diseases (LDs), including small medicines, enzyme replacement therapy (ERT), gene therapy, transplantation, and lysosomal drug targeting (LDT). This study was conducted through databases like PubMed, Google Scholar, Science Direct, and other research engines. To treat LDs, medicines target the lysosomal membrane, acidification processes, cathepsins, calcium signaling, mTOR, and autophagy. Moreover, small-molecule therapies using chaperones, macro-therapies like ERT, gene therapy, and gene editing technologies are used as therapy for LDs. Additionally, endosymbiotic therapy, artificial lysosomes, and lysosomal transplantation are promising options for LD management. LDT enhances the therapeutic outcomes in LDs. Extracellular vesicles and mannose-6-phosphate-tagged nanocarriers display promising approaches for improving LDT. This study concluded that lysosomes play a crucial role in the pathophysiology of numerous diseases. Thus, restoring lysosomal function is essential for treating a wide range of conditions. Despite endosymbiotic therapy, artificial lysosomes, lysosomal transplantation, and LDT offering significant potential for LD control, there are ample challenges regarding safety and ethical implications.

Keywords:  LDT; engineered lysosome; enzyme replacement therapy; gene therapy; lysosomal diseases; proteopathy

DOI:  https://doi.org/10.3390/biom15030327
Int J Mol Sci. 2025 Mar 07. pii: 2377. [Epub ahead of print]26(6):

Modulation of Autophagy on Cinnamaldehyde Induced THP-1 Cell Activation.

Yi Qin, Fan Wu, Rui Wang, Jun Wang, Jiaqi Zhang, Yao Pan.

  Cinnamaldehyde (CIN), which is a cosmetic fragrance allergen regulated by the European Union, can induce allergic contact dermatitis in consumers, reducing their quality of life. Autophagy may be associated with the dendritic cell (DC) response to chemical sensitizers. We hypothesized that CIN would activate DCs through autophagy during skin sensitization. In this study, Tohoku Hospital Pediatrics-1 cells (THP-1 cells) were used as an in vitro DC model, and we evaluated the expression of cell activation markers, intracellular oxidative stress, and autophagy pathway-related genes in response to CIN in THP-1 cells. CIN exposure activated THP-1 cells, which presented increases in CD54 and CD86 expression and ROS generation. Transcriptomic analysis revealed that the genes that were differentially expressed after CIN stimulation were mostly associated with autophagy. The autophagy markers LC3B, p62, and ATG5 had upregulated mRNA and protein levels after CIN exposure. Furthermore, the effects of the autophagy inhibitor Baf-A1 and the autophagy activator rapamycin were investigated on CIN-treated cells. Pretreatment with Baf-A1 in THP-1 cells impaired autophagic flux and dramatically promoted cell activation and oxidative stress triggered by CIN. Conversely, rapamycin inhibited cell activation and the ROS content in CIN-challenged cells while increasing autophagy levels via a reduction in mTOR expression. These results suggest that the autophagy pathway has a pivotal influence on the regulation of CIN-induced activation in THP-1 cells, which provides new insight into the pathogenesis and precise therapeutic strategies for ACD.

Keywords:  DC activation; THP-1 cell; autophagy; cinnamaldehyde; skin sensitization

DOI:  https://doi.org/10.3390/ijms26062377
MicroPubl Biol. 2025 ;2025

Potential for micronuclear turnover through autophagy secretion pathway.

Natsu Asami, Sarasa Yano, Fuminori Tsuruta.

Micronuclei (MN) serve as well-established markers of genomic instability. MN arise from various stresses, such as segregation errors and mechanical stress, and are subsequently eliminated by the autophagy pathway. It has been suggested that MN are traditionally considered markers of cancer cells, often without recognized functional significance. Meanwhile, we recently discovered that MN act as mediators in regulating microglial characteristics. Neurons produce MN in response to migrating stress during the developmental stage and release them to the extracellular space, subsequently transferring them to microglia. In this study, we report the potential mechanisms underlying MN release through the autophagic secretion pathway. Our data show a possibility by which damaged MN are recognized autophagy regulatory factors, resulting in the propagation of MN to microglia.

DOI: https://doi.org/10.17912/micropub.biology.001545
J Cardiovasc Transl Res. 2025 Mar 26.

The Role of Mitophagy in Cardiac Metabolic Remodeling of Heart Failure: Insights of Molecular Mechanisms and Therapeutic Prospects.

Fangying Yan, Liwen Bao.

  Heart failure (HF) treatment remains one of the major challenges in cardiovascular disease management, and its pathogenesis requires further exploration. Cardiac metabolic remodeling is of great significance as a key pathological process in the progression of HF. The complex alterations of metabolic substrates and associated enzymes in mitochondria create a vicious cycle in HF. These changes lead to increased reactive oxygen species, altered mitochondrial Ca2+ handling, and the accumulation of fatty acids, contributing to impaired mitochondrial function. In this context, mitophagy plays a significant role in clearing damaged mitochondria, thereby maintaining mitochondrial function and preserving cardiac function by modulating metabolic remodeling in HF. This article aims to explore the role of mitophagy in cardiac metabolic remodeling in HF, especially in obesity cardiomyopathy, diabetic cardiomyopathy, and excessive afterload-induced heart failure, thoroughly analyze its molecular mechanisms, and review the therapeutic strategies and prospects based on the regulation of mitophagy.

Keywords:  Cardiac metabolic remodeling; Heart failure; Mitophagy; Molecular mechanisms; Therapeutic prospects

DOI:  https://doi.org/10.1007/s12265-025-10606-1
Ageing Res Rev. 2025 Mar 20. pii: S1568-1637(25)00080-7. [Epub ahead of print]108 102734

Impact of diet and exercise on mitochondrial quality and mitophagy in Alzheimer's disease.

Jangampalli Adi Pradeepkiran, Md Ariful Islam, Ujala Sehar, Arubala P Reddy, Murali Vijayan, P Hemachandra Reddy.

  Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide. It is characterized by the accumulation of beta-amyloid and phosphorylated tau, synaptic damage, and mitochondrial abnormalities in the brain, leading to the progressive loss of cognitive function and memory. In AD, emerging research suggests that lifestyle factors such as a healthy diet and regular exercise may play a significant role in delaying the onset and progression of the disease. Mitochondria are often referred to as the powerhouse of the cell, as they are responsible for producing the energy to cells, including neurons to maintain cognitive function. Our article elaborates on how mitochondrial quality and function decline with age and AD, leading to an increase in oxidative stress and a decrease in ATP production. Decline in mitochondrial quality can impair cellular functions contributing to the development and progression of disease with the loss of neuronal functions in AD. This article also covered mitophagy, the process by which damaged or dysfunctional mitochondria are selectively removed from the cell to maintain cellular homeostasis. Impaired mitophagy has been implicated in the progression and pathogenesis of AD. We also discussed the impact of impaired mitophagy implicated in AD, as the accumulation of damaged mitochondria can lead to increased oxidative stress. We expounded how dietary interventions and exercise can help to improve mitochondrial quality, and mitochondrial function and enhance mitophagy in AD. A diet rich in antioxidants, polyphenols, and mitochondria-targeted small molecules has been shown to enhance mitochondrial function and protect against oxidative stress, particularly in neurons with aged and mild cognitively impaired subjects and AD patients. Promoting a healthy lifestyle, mainly balanced diet and regular exercise that support mitochondrial health, in an individual can potentially delay the onset and progression of AD. In conclusion, a healthy diet and regular exercise play a crucial role in maintaining mitochondrial quality and mitochondrial function, in turn, enhancing mitophagy and synaptic activities that delay AD in the elderly populations.

Keywords:  Alzheimer's disease; Diet; Exercise; Mitochondria; Mitophagy; Oxidative stress

DOI:  https://doi.org/10.1016/j.arr.2025.102734
Cells. 2025 Mar 12. pii: 418. [Epub ahead of print]14(6):

Autophagy and Respiratory Viruses: Mechanisms, Viral Exploitation, and Therapeutic Insights.

Farnaz Aligolighasemabadi, Estera Bakinowska, Kajetan Kiełbowski, Mohammadamin Sadeghdoust, Kevin M Coombs, Parvaneh Mehrbod, Saeid Ghavami.

  Respiratory viruses, such as influenza virus, rhinovirus, coronavirus, and respiratory syncytial virus (RSV), continue to impose a heavy global health burden. Despite existing vaccination programs, these infections remain leading causes of morbidity and mortality, especially among vulnerable populations like children, older adults, and immunocompromised individuals. However, the current therapeutic options for respiratory viral infections are often limited to supportive care, underscoring the need for novel treatment strategies. Autophagy, particularly macroautophagy, has emerged as a fundamental cellular process in the host response to respiratory viral infections. This process not only supports cellular homeostasis by degrading damaged organelles and pathogens but also enables xenophagy, which selectively targets viral particles for degradation and enhances cellular defense. However, viruses have evolved mechanisms to manipulate the autophagy pathways, using them to evade immune detection and promote viral replication. This review examines the dual role of autophagy in viral manipulation and host defense, focusing on the complex interplay between respiratory viruses and autophagy-related pathways. By elucidating these mechanisms, we aim to highlight the therapeutic potential of targeting autophagy to enhance antiviral responses, offering promising directions for the development of effective treatments against respiratory viral infections.

Keywords:  HPIV; adenovirus; autophagy; coronavirus; influenza virus; respiratory syncytial virus (rsv); respiratory viruses

DOI:  https://doi.org/10.3390/cells14060418
Sci Rep. 2025 Mar 27. 15(1): 10585

Lactoferrin influences atherosclerotic progression by modulating macrophagic AMPK/mTOR signaling-dependent autophagy.

Bing Xia, Jingwei Liang, Yanlin Lu, Jiuyang Ding, Jin Peng, Fangqin Li, Jialin Dai, Yubo Liu, Jie Wang, Changwu Wan, Peng Luo.

  This study aimed to explore the role of lactoferrin (LTF) in atherosclerosis (AS) and its possible mechanisms. Human left coronary artery tissues were collected and divided into control (CON), coronary heart disease (CHD) and sudden coronary death (SCD) groups. Pathologic changes (including changes in the coronary plaque area, necrotic core, collagen fibers, and foam cell content) were observed. The LTF, P62, and 4-hydroxynonenal (4-HNE) expression levels were assessed. The ApoE-/- AS mouse model was established. The pathological changes and related protein levels were analyzed after autophagy inhibition. The foam cell model was constructed using an ox-LDL-induced human monocyte line, THP-1. The LTF, BECN1, LC3-II/I, AMP-activated protein kinase (AMPK)/the mammalian target of rapamycin (mTOR) pathway proteins, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and 4-HNE expressions were then detected after silencing of LTF or BECN1. Plaque stability was significantly lower in the SCD group compared to the non-SCD group (p < 0.05). LTF, P62 and 4-HNE levels in plaques increased as plaque stability decreased, and LTF was significantly correlated with plaque progression and autophagy levels. Autophagy inhibition by U0126 leads to the worsening of aortic luminal stenosis, increased necrotic core and foam cell deposits, decreased autophagosomes, reduced LTF expression, and upregulated P62 expression in AS mice. It was further demonstrated that LTF expression correlates with autophagy. LTF expression was increased in ox-LDL-treated THP-1 cells, and silencing BECN1 and/or LTF increased mTOR phosphorylation and 4-HNE levels, inhibited BECN1 and LC3 II expression and AMPK activation, and simultaneously decreased the Bcl-2/Bax ratio. LTF might alleviate AS pathology through accelerating the AMPK/mTOR pathway, and suggested that LTF may be a potential predictive molecule for AS.

Keywords:  AMPK; Atherosclerosis; Autophagy; Lactoferrin; Sudden coronary death; mTOR

DOI:  https://doi.org/10.1038/s41598-025-95181-w
Nat Cell Biol. 2025 Mar 26.

Proteostasis and lysosomal repair deficits in transdifferentiated neurons of Alzheimer's disease.

Ching-Chieh Chou, Ryan Vest, Miguel A Prado, Joshua Wilson-Grady, Joao A Paulo, Yohei Shibuya, Patricia Moran-Losada, Ting-Ting Lee, Jian Luo, Steven P Gygi, Jeffery W Kelly, Daniel Finley, Marius Wernig, Tony Wyss-Coray, Judith Frydman.

Ageing is the most prominent risk factor for Alzheimer's disease (AD). However, the cellular mechanisms linking neuronal proteostasis decline to the characteristic aberrant protein deposits in the brains of patients with AD remain elusive. Here we develop transdifferentiated neurons (tNeurons) from human dermal fibroblasts as a neuronal model that retains ageing hallmarks and exhibits AD-linked vulnerabilities. Remarkably, AD tNeurons accumulate proteotoxic deposits, including phospho-tau and amyloid β, resembling those in APP mouse brains and the brains of patients with AD. Quantitative tNeuron proteomics identify ageing- and AD-linked deficits in proteostasis and organelle homeostasis, most notably in endosome-lysosomal components. Lysosomal deficits in aged tNeurons, including constitutive lysosomal damage and ESCRT-mediated lysosomal repair defects, are exacerbated in AD tNeurons and linked to inflammatory cytokine secretion and cell death. Providing support for the centrality of lysosomal deficits in AD, compounds ameliorating lysosomal function reduce amyloid β deposits and cytokine secretion. Thus, the tNeuron model system reveals impaired lysosomal homeostasis as an early event of ageing and AD.

DOI: https://doi.org/10.1038/s41556-025-01623-y
Int J Mol Sci. 2025 Mar 13. pii: 2589. [Epub ahead of print]26(6):

mTOR-Mediated Autophagy Regulates Cadmium-Induced Kidney Injury via Pyroptosis.

Yuan Hu, Kui Wang, Jie Xu, Guohuan Wan, Yiyi Zhao, Yajing Chen, Kangfeng Jiang, Xiaobing Li.

  The heavy metal cadmium (Cd) affects the global livestock production economy mainly through the contamination of feed raw materials and secondary contamination in feed processing, and it also poses a serious threat to food safety and human health. The nucleotide-binding oligomerization domain-like pyrin-domain-containing protein 3 (NLRP3) inflammasome is a key regulatory element of pyroptosis, which is engaged in kidney injury. Meanwhile, autophagy is also involved in renal inflammation. Mammalian target of rapamycin (mTOR) plays an important role in pyroptosis and autophagy, but its function in Cd-induced kidney injury remains unclear. In this study, we explored the role of mTOR-mediated autophagy and pyroptosis in kidney injury caused by Cd exposure and elucidated its underlying mechanism. Our data showed that Cd exposure reduced the integrity of kidney cell membranes, increased the expression of pyroptosis-associated proteins, and promoted the release of inflammatory cytokines. Subsequently, a notable attenuation in Cd-induced pyroptosis was observed following the administration of CY-09, an NLRP3 inhibitor. In addition, Cd exposure promoted autophagy in kidney cells. Importantly, in both in vivo and in vitro experiments, rapamycin, an mTOR inhibitor, downregulated the expression of pyroptosis-related proteins, thereby significantly improving Cd-induced kidney injury. In summary, our results indicate that mTOR-mediated autophagy has a significant protective effect on NLRP3 inflammasome-dependent kidney injury induced by Cd exposure, thus providing new insights into the prevention and treatment of Cd poisoning.

Keywords:  NLRP3; autophagy; cadmium; kidney injury; mTOR; pyroptosis

DOI:  https://doi.org/10.3390/ijms26062589
Cell Mol Life Sci. 2025 Mar 26. 82(1): 130

Endophilin B1 is essential for maintaining cardiac function by regulating mitocytosis.

Jingyu Deng, Xiaoqian Chang, Xiaomeng Zhang, Congye Li, Guigao Guo, Haifeng Song, Yangzhi Zheng, Chenhao Zhang, Bo Yang, Chujie Zhang, Pingping Xing, Zheng Zhang, Tao Yin, Ling Tao, Shan Wang.

  Endophilin B1 is a member of the Endophilin family and has been shown to be involved in apoptosis, mitochondrial morphological changes and autophagy. Although Endophilin B1 is highly expressed in the heart, its role in the maintenance of normal cardiac function and myocardial ischemia and reperfusion (I/R) injury remains unclear. Here, we found that Endophilin B1 deletion provoked spontaneous cardiac contractile dysfunction, cardiac hypertrophy and fibrosis at 16 weeks of age. Moreover, at 8 weeks of age, although spontaneous cardiac dysfunction in Endophilin B1 deletion mice had not developed, the deletion of Endophilin B1 exacerbated I/R-induced cardiac contractile dysfunction and cardiomyocyte death, whereas restoration of Endophilin B1 expression in the heart reduced I/R injury. Furthermore, we discovered that Endophilin B1 is indispensable for maintaining normal mitochondrial structure and function. In addition, we found that Endophilin B1 is localized in extracellular mitochondrion-containing vesicles and is required for mitocytosis, a process by which damaged mitochondria are disposed through extracellular vesicles. In conclusion, our study identified Endophilin B1 as an essential mitocytosis regulator for maintaining mitochondrial homeostasis and cardiac function. These findings suggest that Endophilin B1 is a novel therapeutic target for cardiac disorders such as I/R injury, myocardial infarction and heart failure.

Keywords:  Cardiac function; Endophilin B1; Extracellular vesicle; Mitocytosis

DOI:  https://doi.org/10.1007/s00018-025-05646-4
EMBO J. 2025 Mar 24.

S-palmitoylation modulates ATG2-dependent non-vesicular lipid transport during starvation-induced autophagy.

Wenhui Zheng, Maomao Pu, Sai Zeng, Hongtao Zhang, Qian Wang, Tao Chen, Tianhua Zhou, Chunmei Chang, Dante Neculai, Wei Liu.

  Lipid transfer proteins mediate the non-vesicular transport of lipids at membrane contact sites to regulate the lipid composition of organelle membranes. Despite significant recent advances in our understanding of the structural basis for lipid transfer, its functional regulation remains unclear. In this study, we report that S-palmitoylation modulates the cellular function of ATG2, a rod-like lipid transfer protein responsible for transporting phospholipids from the endoplasmic reticulum (ER) to phagophores during autophagosome formation. During starvation-induced autophagy, ATG2A undergoes depalmitoylation as the balance between ZDHHC11-mediated palmitoylation and APT1-mediated depalmitoylation. Inhibition of ATG2A depalmitoylation leads to impaired autophagosome formation and disrupted autophagic flux. Further, in cell and in vitro analyses demonstrate that S-palmitoylation at the C-terminus of ATG2A anchors the C-terminus to the ER. Depalmitoylation detaches the C-terminus from the ER membrane, enabling it to interact with phagophores and promoting their growth. These findings elucidate a S-palmitoylation-dependent regulatory mechanism of cellular ATG2, which may represent a broad regulatory strategy for lipid transport mediated by bridge-like transporters within cells.

Keywords:  ATG2; Autophagy; Lipid Transfer Protein; S-palmitoylation

DOI:  https://doi.org/10.1038/s44318-025-00410-7
Am J Chin Med. 2025 Mar 27. 1-20

Chlorogenic Acid Ameliorates Acetaminophen-Induced Liver Injury Through AMPK/mTOR/ULK1-Mediated Autophagy Activation.

Yu-Xin Yao, Chen-Hao Yao, Chao-Yang Zhang, Xian-Zhi Peng, Shu Dai, Yu-Jie Yu, Yan-Zhi Li, Sheng-Lin Zhang, Yun-Xia Li.

  Acetaminophen (APAP)-induced liver injury (AILI) is a universal liver disease and the predominant cause of acute liver failure in clinical practice. Autophagy is a highly conserved intracellular degradation pathway, with accumulating evidence indicating its involvement in APAP hepatotoxicity. Notably, the serine/threonine AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/unc-51-like kinase 1 (ULK1) pathway serves as the most classical autophagy pathway and engages in autophagy activation. Thus, pharmacological activation of the AMPK/mTOR/ULK1 pathway has emerged as a critical strategy for addressing AILI. Chlorogenic acid (CGA), a main bioactive constituent isolated from Lonicera japonica Thunb., is an autophagy regulator with potential for AILI therapy. However, whether and how CGA modulates autophagy to antagonize AILI has not yet been elucidated. In the present study, we aim to explore the impact of CGA on AILI, as well as the underlying mechanisms in vitro and in vivo. The results demonstrated that CGA could protect the mice and LO2 cells from oxidative stress and liver injury induced by APAP. Regarding mechanisms, CGA activated the AMPK/mTOR/ULK1 pathway, thereby promoting autophagy. This was evidenced by the degradation of p62/SQSTM1 (hereafter referred to as p62), as well as the up-regulation of LC3B, ATG5, and Beclin1. It is worth noting that the aforementioned, CGA-provided beneficial effects were abrogated by pharmacological inhibition of AMPK with Compound C (CC, an AMPK inhibitor). These [Formula: see text] that CGA alleviates oxidative stress and liver injury induced by APAP, which is contingent upon the regulatory effect of CGA on the AMPK/mTOR/ULK1 axis.

Keywords:  AMPK/mTOR/ULK1 Signaling; APAP-induced Liver Injury; Autophagy; Chlorogenic Acid

DOI:  https://doi.org/10.1142/S0192415X2550020X
Science. 2025 Mar 28. 387(6741): eadq8331

Leucine aminopeptidase LyLAP enables lysosomal degradation of membrane proteins.

Aakriti Jain, Isaac Heremans, Gilles Rademaker, Tyler C Detomasi, Peter Rohweder, Dashiell Anderson, Justin Zhang, Grace A Hernandez, Suprit Gupta, Teresa von Linde, Mike Lange, Martina Spacci, Jiayi Luo, Y Rose Citron, James A Olzmann, David W Dawson, Charles S Craik, Guido Bommer, Rushika M Perera, Roberto Zoncu.

Breakdown of every transmembrane protein trafficked to lysosomes requires proteolysis of their hydrophobic helical transmembrane domains. Combining lysosomal proteomics with functional genomic datasets, we identified lysosomal leucine aminopeptidase (LyLAP; formerly phospholipase B domain-containing 1) as the hydrolase most tightly associated with elevated endocytosis. Untargeted metabolomics and biochemical reconstitution demonstrated that LyLAP is a processive monoaminopeptidase with preference for amino-terminal leucine. This activity was necessary and sufficient for the breakdown of hydrophobic transmembrane domains. LyLAP was up-regulated in pancreatic ductal adenocarcinoma (PDA), which relies on macropinocytosis for nutrient uptake. In PDA cells, LyLAP ablation led to the buildup of undigested hydrophobic peptides, lysosomal membrane damage, and growth inhibition. Thus, LyLAP enables lysosomal degradation of membrane proteins and protects lysosomal integrity in highly endocytic cancer cells.

DOI: https://doi.org/10.1126/science.adq8331
Autophagy. 2025 Mar 26.

ATG16L1 WD domain and linker regulates lipid trafficking to maintain plasma membrane integrity to limit influenza virus infection.

Benjamin Bone, Luke Griffith, Matthew Jefferson, Yohei Yamauchi, Thomas Wileman, Penny P Powell.

  The non-canonical functions of autophagy protein ATG16L1 are dependent on a C-terminal WD domain. Recent studies show that the WD domain is required for conjugation of LC3 to single membranes during endocytosis and phagocytosis, where it is thought to promote fusion with lysosomes. Studies in cells lacking the WD domain suggest additional roles in the regulation of cytokine receptor recycling and plasma membrane repair. The WD domain also protects mice against lethal influenza virus in vivo. Here, analysis of mice lacking the WD domain (ΔWD) shows enrichment of cholesterol in brain tissue suggesting a role for the WD domain in cholesterol transport. Brain tissue and cells from ΔWD mice showed reduced cholesterol and phosphatidylserine (PS) in the plasma membrane. Cells from ΔWD mice also showed an intracellular accumulation of cholesterol predominantly in late endosomes. Infection studies using IAV suggest that the loss of cholesterol and PS from the plasma membrane in cells from ΔWD mice results in increased endocytosis and nuclear delivery of IAV, as well as increased Ifnb/Ifnβ and Isg15 gene expression. Upregulation of Il6, Ifnb and Isg15 mRNA were observed in "ex vivo" precision cut lung slices from ΔWD mice both at rest and in response to IAV infection. Overall, we present evidence that regulation of lipid transport by the WD domain of ATG16L1 May have downstream implications in attenuating viral infection and limiting lethal cytokine signaling.

Keywords:  ATG16L1 WD domain; cholesterol, cytokine storm; influenza virus; interferon, non-canonical autophagy

DOI:  https://doi.org/10.1080/15548627.2025.2482516
J Pharmacol Exp Ther. 2025 Feb 28. pii: S0022-3565(25)39737-5. [Epub ahead of print]392(4): 103524

DBeQ derivative targets vacuolar protein sorting 4 functions in cancer cells and suppresses tumor growth in mice.

Kevin A Fundora, Yan Zhuang, Kouta Hamamoto, Guifang Wang, Longgui Chen, Tatsuya Hattori, Xinwen Liang, Lei Bao, Venugopal Vangala, Fang Tian, Yoshinori Takahashi, Hong-Gang Wang.

  Vacuolar protein sorting 4 (VPS4) is an AAA-ATPase that catalyzes the endosomal sorting complex required for transport-III disassembly, mediating various cellular membrane-remodeling processes including endolysosomal membrane repair and autophagosome closure. Humans have 2 VPS4 paralogs, VPS4A and VPS4B, and the loss of either paralog has been identified in a significant proportion of cancers, rendering them dependent on the remaining paralog for survival. In this study, we explored VPS4 inhibition as an anticancer strategy by investigating the mechanisms of VPS4 inhibition-induced cell death and developing small-molecule compounds that target VPS4 functions. We found that genetic inhibition of VPS4 triggered both caspase-8 (CASP8)-dependent apoptosis and caspase-independent cell death in osteosarcoma cells. We synthesized approximately 100 derivatives of the VPS4 and related AAA-ATPase valosin-containing protein inhibitor DBeQ and screened for their inhibitory effects on VPS4 ATPase activity using the EnzChek phosphate assay and a high-content assay monitoring GFP-CHMP4B puncta formation. In cells, the lead compound 4-107 caused endolysosomal damage, disrupted subsequent membrane repair, inhibited autophagy, and led to the accumulation of the endosomal sorting complex required for transport on membranes. These effects were accompanied by the stabilization of CASP8 on autophagosomal membranes, leading to the induction of CASP8-mediated apoptosis. Notably, the CASP8-mediated cell death induced by 4-107 was further enhanced by the loss of either VPS4 paralog. Moreover, 4-107 exhibited antitumor activity in a syngeneic mouse model of neuroblastoma. Our findings provide an important step for targeting VPS4 in cancer and developing VPS4 inhibitors as a cancer treatment strategy. SIGNIFICANCE STATEMENT: VPS4A and VPS4B, paralogs of the AAA-ATPase VPS4, are critical for cancer cell survival. This study reports that 4-107, a DBeQ derivative, inhibits VPS4 ATPase activity, induces CASP8-mediated apoptosis, and suppresses tumor growth in mice. This study supports the further development of VPS4A/B inhibitors as a promising anticancer treatment strategy.

Keywords:  Apoptosis; Autophagy; ESCRT; Lysosomal membrane integrity; VPS4

DOI:  https://doi.org/10.1016/j.jpet.2025.103524
Sci Rep. 2025 Mar 25. 15(1): 10240

Has-miR-30c-1-3p inhibits macrophage autophagy and promotes Mycobacterium tuberculosis survival by targeting ATG4B and ATG9B.

Xianglin Peng, Feifei Pu, Fangzheng Zhou, Xiyong Dai, Feng Xu, Junwen Wang, Jing Feng, Ping Xia.

  Autophagy is a widespread physiological process in the body, which also protects the host by degrading invading pathogens and harmful substances during pathological conditions. Nevertheless, Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis, has evolved strategies to subvert autophagy by modulating microRNA (miRNA) expression, enabling its escape from host defenses. In this study, we established an in vitro model using the human macrophage cell line infected with the highly virulent MTB strain H37Rv. Through RNA sequencing and bioinformatic analysis post H37Rv infection, we screened 14 differentially expressed miRNAs. We predicted and demonstrated that miR-30c-1-3p inhibits autophagy and promotes MTB survival by targeting ATG4B and ATG9B during the infection process. The results showed that miR-30c-1-3p expression was gradually increased before 12 h of H37Rv infection, followed by a decrease. Overexpression of miR-30c-1-3p suppressed autophagic activity. We also identified the targeting of miR-30c-1-3p to ATG4B and ATG9B for the first time, and overexpression of both ATG4B and ATG9B, alone or together, on the basis with upregulation of miR-30c-1-3p reversed the inhibition of autophagy. Autophagy levels were analyzed at different levels by western blot, immunofluorescence, and transmission electron microscopy, all of which showed that upregulation of miR-30c-1-3p inhibited autophagy during H37Rv infection. Additionally, the intervention of miR-30c-1-3p mimics resulted in an increased bacterial load in macrophages, suggesting that MTB achieves immune evasion by upregulating miR-30c-1-3p during infection. In conclusion, our study provides a valuable target for the development of host-directed anti-tuberculosis therapy as well as a new diagnostic marker.

Keywords:   Mycobacterium tuberculosis ; ATG4B; ATG9B; Autophagy; Immune evasion; miR-30c-1-3p

DOI:  https://doi.org/10.1038/s41598-025-94452-w
Cell Rep. 2025 Mar 25. pii: S2211-1247(25)00245-1. [Epub ahead of print]44(4): 115474

Antagonistic roles for MITF and TFE3 in melanoma plasticity.

Jeremy Chang, Katelyn R Campbell-Hanson, Marion Vanneste, Nicholas I Bartschat, Ryan Nagel, Asdis K Arnadottir, Hong Nhung Vu, Collin Montgomery, Julius Yevdash, Jiarui Jiang, Ardith Bhinu, Annika Helverson, Michael D Henry, Eiríkur Steingrímsson, Ronald J Weigel, Robert A Cornell, Colin Kenny.

  Melanoma cells can switch from a melanocytic and proliferative state to a mesenchymal and invasive state and back again. This plasticity drives intratumoral heterogeneity, progression, and therapeutic resistance. Microphthalmia-associated transcription factor (MITF) promotes the melanocytic/proliferative phenotype, but factors that drive the mesenchymal/invasive phenotype and the mechanisms that effect the switch between cell states are unclear. Here, we identify the MITF paralog, TFE3, and the non-canonical mTORC1 pathway as regulators of the mesenchymal state. We show that TFE3 expression drives the metastatic phenotype in melanoma cell lines and tumors. Deletion of TFE3 in MITF-low melanoma cell lines suppresses their ability to migrate and metastasize. Further, MITF suppresses the mesenchymal phenotype by directly or indirectly activating expression of FNIP1, FNIP2, and FLCN, which encode components of the non-canonical mTORC1 pathway, thereby promoting cytoplasmic retention and lysosome-mediated degradation of TFE3. These findings highlight a molecular pathway controlling melanoma plasticity and invasiveness.

Keywords:  CP: Cancer; CP: Genomics; MITF; TFE3; cell plasticity; mTORC1; melanoma; metastasis; phenotype switching; protein stability

DOI:  https://doi.org/10.1016/j.celrep.2025.115474
Autophagy. 2025 Mar 26.

Staphylococcus aureus reprograms CASP8 (caspase 8) signaling to evade cell death and Xenophagy.

Yi-Tian Ying, Jing Yang, Hui-Wen Ye, Mei-Yi Chen, Xia Liu, Wei Chen, Jin-Xin Xu, Xun Tan.

  Regulated cell death and xenophagy constitute fundamental cellular mechanisms against invading microorganisms. Staphylococcus aureus, a notorious pathogen, can invade and persist within host cells for extended periods. Here, we describe a novel mechanism by which S. aureus subverts these host defenses through the manipulation of the CASP8 (caspase 8) signaling pathway. Upon invasion, S. aureus triggers the assembly of a RIPK3 (receptor interacting serine/threonine kinase 3) complex to induce CASP8 autoprocessing. However, the bacterium inhibits CUL3 (cullin 3)-dependent K63-linked ubiquitination, leading to an atypical activation of CASP8. This non-canonical activation does not initiate the CASP8-CASP3 cascade but instead suppresses RIPK3-dependent necroptosis, a regulated cell death pathway typically activated when apoptosis fails. The resulting non-apoptotic, cleaved CASP8 redirects its enzymatic activity toward cleaving SQSTM1/p62, a selective macroautophagy/autophagy receptor, thus enabling S. aureus to evade antimicrobial xenophagy. The results of this study suggest that S. aureus reprograms the CASP8 signaling pathway from inducing cell death to preserving cell survival and inhibiting xenophagy, a critical strategy that supports its stealthy replication and persistence within host cells.

Keywords:  Apoptosis; RIPK1; RIPK3; SQSTM1/p62; autophagy; necroptosis

DOI:  https://doi.org/10.1080/15548627.2025.2483887
Autophagy. 2025 Mar 24. 1-22

HMBOX1 reverses autophagy mediated 5-fluorouracil resistance through promoting HACE1-induced ubiquitination and degradation of ATG5 in colorectal cancer.

Yan Gao, Shenao Fu, Yinghui Peng, Yulai Zhou, Jiang Zhu, Xiangyang Zhang, Changjing Cai, Ying Han, Hong Shen, Shan Zeng.

  Chemotherapy remains the primary treatment for unresectable or advanced postoperative colorectal cancers. However, its effectiveness is compromised by chemoresistance, which adversely affects patient outcomes. Dysregulated macroautophagy/autophagy is a proposed mechanism behind this resistance, with ubiquitination playing a key regulatory role. In this study, we identify the transcription factor HMBOX1 (homeobox containing 1) as a critical regulator of chemoresistance in colorectal cancer. RNA sequencing revealed that HMBOX1 is downregulated in drug-resistant colorectal cancer cells and tissues, with its low expression linked to poor prognosis. An integrated analysis of genes associated with autophagy and 5-fluorouracil (5-FU) resistance was conducted, verified in the colorectal cancer tissues of patients by single-cell RNA sequencing and immunostaining. Mass-spectrometry-based proteomics and RNA sequencing were used to elucidate the underlying molecular mechanisms. Functionally, upregulation of HMBOX1 enhances the sensitivity of colorectal cancer cells to the first-line treatment with 5-FU by inhibiting autophagy. Mechanistically, HMBOX1 promotes the transcription of the E3 ubiquitin ligase HACE1, which in turn enhances ATG5 K63-ubiquitination and subsequent proteasome-mediated degradation. This results in decreased ATG5 levels, inhibiting autophagy and thus reducing 5-FU resistance in colorectal cancer cells both in vitro and in vivo. Furthermore, we confirm that HMBOX1 expression positively correlates with HACE1 expression and inversely correlates with autophagy levels in clinical colorectal cancer tissues. Our findings suggest that HMBOX1 downregulation drives 5-FU resistance through autophagy enhancement in colorectal cancer, highlighting HMBOX1 as a potential target for improving chemosensitivity and patient prognosis.Abbreviation: 3-MA: 3-methyladenine; 5-FU: 5-fluorouracil; ATG: autophagy related; CASP3: caspase 3; C-CASP3: cleaved caspase 3; C-PARP: cleaved PARP; CCK8: cell counting kit-8; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; CNV: copy number variation; co-IP: co-immunoprecipitation; COAD: colorectal adenocarcinoma; CQ: chloroquine; CRC: colorectal cancer; CR: complete response; FHC: fetal human colon; GEO: Gene Expression Omnibus; HACE1: HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1; HMBOX1: homeobox containing 1; IHC: immunohistochemistry; LC-MS/MS: liquid chromatography-tandem mass spectrometry; mIHC: multiplexed immunohistochemistry; MUT: mutant; NC: negative control; OS: overall survival; PBS: phosphate-buffered saline; PD: progressive disease; PFA: paraformaldehyde; PFS: progression-free survival; PR: partial response; qPCR: quantitative polymerase chain reaction; RAPA: rapamycin; SD: stable disease; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TF: translation factor; USP22: ubiquitin specific peptidase 22; WT: wild type.

Keywords:  5-fluorouracil resistance; HMBOX1 (homeobox containing 1); autophagy; colorectal cancer; ubiquitination

DOI:  https://doi.org/10.1080/15548627.2025.2477443
Neuroscience. 2025 Mar 24. pii: S0306-4522(25)00254-4. [Epub ahead of print]

Defective PINK1-dependent mitophagy is involved in high glucose-induced neurotoxicity.

Yongsheng Bian, Yimei Yang, Jun Chen, Jian Liu, Yan Tao, Zhongjie Liu, Lijin Huang.

  Neuropathic pain often complicates diabetes progression, yet the pathogenic mechanisms are poorly understood. Defective mitophagy is linked to various diabetic complications like nephropathy, cardiomyopathy, and retinopathy. To investigate the molecular basis of hyperglycemia-induced painful diabetic neuropathy (PDN), we examined the effect of high glucose on the PTEN-induced kinase 1 (PINK1)/Parkin RBR E3 ubiquitin protein ligase (Parkin)-mediated mitophagy pathway in ND7/23 cells. Cells were treated with different glucose concentrations (25, 50, 75 mM) for various durations (24, 48, 72 h). Additionally, cells were exposed to high glucose (50 mM) with or without 100 nM rapamycin (a mitophagy enhancer) for 48 h, or transfected with PINK1 siRNA. We assessed protein levels of mitophagy-related genes (PINK1, Parkin, P62, LC3B) and apoptotic markers (cleaved-Caspase3) via Western blotting. High glucose significantly reduced the expression of autophagy-related proteins PINK1 and Parkin in a time- and concentration-dependent manner compared to controls. Rapamycin counteracted the inhibitory effects of high glucose on PINK1/Parkin-mediated mitophagy, while PINK1 siRNA transfection showed similar outcomes, confirming the inhibitory impact of high glucose on mitophagy. Moreover, high glucose induced apoptosis by suppressing PINK1/Parkin-mediated mitophagy, causing cytotoxic effects in ND7/23 cells which is derived from the fusion of mouse neuroblastoma cells and rat dorsal root ganglion (DRG) cells. Our findings suggest that hyperglycemia-induced disruption of the PINK1/Parkin mitophagy pathway impairs mitochondrial homeostasis, leading to apoptosis. Therefore, targeting PINK1 pathway activation or restoring mitophagy might be a promising therapeutic strategy for PDN treatment.

Keywords:  Apoptosis; Diabetic; Mitophagy; Neurotoxicity; PDN; PINK1; Rapamycin

DOI:  https://doi.org/10.1016/j.neuroscience.2025.03.052
Neurosci Res. 2025 Mar 22. pii: S0168-0102(25)00064-1. [Epub ahead of print]

Optineurin knock-out forms TDP-43 aggregates to regulate TDP-43 protein levels despite autophagic up-regulation and aberrant TDP-43 expression.

Yuta Maetani, Takashi Kurashige, Yui Tada, Kodai Kume, Tomoaki Watanabe, Yusuke Sotomaru, Koji Yamanaka, Hirofumi Maruyama, Hideshi Kawakami.

  Optineurin is a causative gene of amyotrophic lateral sclerosis (ALS) and has many roles in processes such as autophagy and inflammation. However, it is unclear how optineurin causes ALS. Optineurin knock-out (Optn-KO) mice, which have been generated by several researchers, exhibit motor neuron degeneration and TDP-43 aggregates, but no motor deficits. Motor dysfunction in ALS model mice is associated with TDP-43 in the spinal cord. We bred Optn-KO mice with TDP-43 overexpression transgenic mice and evaluated whether increased TDP-43 protein causes motor deficits and whether Optn-KO affects TDP-43 protein level. Optn-KO mice had spinal TDP-43 protein levels and motor function comparable to wild-type mice, and TDP-43-transgenic (TDP-43-tg) mice resulted in motor dysfunction and early death. However, double-mutant TDP-43-tg / Optn-KO mice had lower TDP-43 protein levels than TDP-43-tg mice at 18 months age, and showed inhibition of the TBK1-optinerurin autophagic pathway with aging. Furthermore, Optn-KO caused TDP-43-positive cytoplasmic aggregates. TDP-43 overexpression by itself induced spinal microgliosis, but Optn-KO suppressed that microgliosis. Finally, we showed that Optn-KO mice could not exhibit behavioral dysfunction because TDP-43 protein levels were not elevated despite autophagy inhibition. Thus, downregulation of Optn may suppress TDP-43 toxicity by regulating its abundance through aggregate formation.

Keywords:  ALS; TDP-43; aggregate; autophagy; optineurin

DOI:  https://doi.org/10.1016/j.neures.2025.03.005
Biochim Biophys Acta Rev Cancer. 2025 Mar 20. pii: S0304-419X(25)00044-7. [Epub ahead of print]1880(3): 189302

Radiotherapy modulates autophagy to reshape the tumor immune microenvironment to enhance anti-tumor immunity in esophageal cancer.

Suna Zhou, Haihua Yang.

  The combination of radiotherapy and immunotherapy exerts synergistic antitumor in a range of human cancers, and also in esophageal cancer. Radiotherapy-induced tumor immune microenvironment (TIME) reprogramming is an essential basis for the synergistic antitumor between radiotherapy and immunotherapy. Radiotherapy can induce autophagy in tumor cells and immune cells of TIME, and autophagy activation is involved in the modification of immunological characteristics of TIME. The TIME landscape of esophageal cancer, especially ESCC, can be affected by radiotherapy or autophagy regulation. In this review, we depicted that local radiotherapy-induced autophagy could promote the maturation, migration, infiltration, and function of immune cells by complicated mechanisms to make TIME from immune "cold" to "hot", resulting in the synergistic antitumor of RT and IO. We argue that unraveling the relevance of radiotherapy-initiated autophagy to driving radiotherapy reprogramming TIME will open new ideas to explore new targets or more efficiently multimodal therapeutic interventions in ESCC.

Keywords:  Autophagy; Esophageal cancer; Immunotherapy; Radiotherapy; TIME

DOI:  https://doi.org/10.1016/j.bbcan.2025.189302
FEBS Open Bio. 2025 Mar 24.

Positive feedback loop between MAPK and aquaporin 7 regulates autophagy and apoptosis induced by palmitate in RIN-m5f cells.

Maoqi Wang, Jiang Tan, Xueting He, Yuqin Chen, Guoping Qiu, Mei Yang.

  Type 2 diabetes mellitus (T2DM) is characterized by peripheral blood insulin resistance and progressive pancreatic β-cell dysfunction which is closely related to apoptosis of β-cells. Aquaporin 7 (AQP7) is the only aquaglyceroporin protein expressed in pancreatic β-cells. However, the relationship between AQP7 and autophagy remains unexplored, with limited studies investigating its link to islet β-cell apoptosis. In our study, we utilized an in vitro model involving palmitate-treated rat pancreatic β-cells (RIN-m5f) to examine these relationships. Our aim was to investigate the effects of AQP7 on autophagy and apoptosis by examining LC3 lipidation levels and p62 expression in pancreatic islet β-cells, thereby elucidating potential underlying mechanisms. Our results showed that phosphorylation of p38 and c-Jun-terminal kinase (JNK) increased in response to palmitate treatment, indicating the activation of these signaling pathways. Conversely, AQP7 expression decreased, reduced autophagy, and promoted apoptosis. AQP7 knockdown activated the p38 and JNK signaling pathways, inhibited autophagy (as evidenced by LC3 lipidation and p62 expression), and increased apoptosis. Furthermore, AQP7 overexpression repressed palmitate-induced apoptosis and alleviated autophagy inhibition by suppressing the p38 and JNK mitogen-activated protein kinase (MAPK) signaling pathways. Our results suggest a positive feedback loop between MAPK signaling and AQP7 that regulates autophagy and apoptosis in RIN-m5f cells under high-fat conditions.

Keywords:  MAPK; apoptosis; aquaporin 7; autophagy; palmitate

DOI:  https://doi.org/10.1002/2211-5463.70011
Nat Commun. 2025 Mar 22. 16(1): 2839

Mitochondria transplantation transiently rescues cerebellar neurodegeneration improving mitochondrial function and reducing mitophagy in mice.

Shu-Jiao Li, Qian-Wen Zheng, Jie Zheng, Jin-Bao Zhang, Hui Liu, Jing-Jing Tie, Kun-Long Zhang, Fei-Fei Wu, Xiao-Dong Li, Shuai Zhang, Xin Sun, Yan-Ling Yang, Ya-Yun Wang.

Cerebellar ataxia is the primary manifestation of cerebellar degenerative diseases, and mitochondrial dysfunction in Purkinje cells (PCs) plays a critical role in disease progression. In this study, we investigated the feasibility of mitochondria transplantation as a potential therapeutic approach to rescue cerebellar neurodegeneration and elucidate the associated mechanisms. We constructed a conditional Drp1 knockout model in PCs (PCKO mice), characterized by progressive ataxia. Drp1 knockout resulted in pervasive and progressive apoptosis of PCs and significant activation of surrounding glial cells. Mitochondrial dysfunction, which triggers mitophagy, is a key pathogenic factor contributing to morphological and functional damage in PCs. Transplanting liver-derived mitochondria into the cerebellum of 1-month-old PCKO mice improved mitochondrial function, reduced mitophagy, delayed apoptosis of PCs, and alleviated cerebellar ataxia for up to 3 weeks. These findings demonstrate that mitochondria transplantation holds promise as a therapeutic approach for cerebellar degenerative diseases.

DOI: https://doi.org/10.1038/s41467-025-58189-4
Adv Sci (Weinh). 2025 Mar 26. e2414960

Syntaxin 17 Translocation Mediated Mitophagy Switching Drives Hyperglycemia-Induced Vascular Injury.

Anqi Luo, Rui Wang, Jingwen Gong, Shuting Wang, Chuan Yun, Zongcun Chen, Yanan Jiang, Xiaoquan Liu, Haofu Dai, Haochen Liu, Yunsi Zheng.

  The risk of diabetic cardiovascular complications is closely linked to the length of hyperglycemia exposure. Mitophagy plays a significant role in vascular endothelial injury. However, the specific mechanisms by which mitophagy contributes to endothelial injury during sustained hyperglycemia remain unclear. In diabetic ApoE-/- mice and human umbilical vein endothelial cell (HUVEC) models, mitophagy is enhanced following short-term and long-term high-glucose exposure. Short-term high-glucose exposure promotes Parkin-mediated mitophagy and upregulates mitochondrial fission protein 1 (Fis1) expression, whereas long-term high-glucose exposure suppresses Parkin-mediated mitophagy and downregulates Fis1. With prolonged high-glucose exposure, Syntaxin 17 (STX17) translocates from the endoplasmic reticulum to the mitochondria, activating STX17-mediated mitophagy. Silencing STX17 alleviates mitochondrial degradation, decreases reactive oxygen species (ROS) levels, enhances endothelial nitric oxide synthase (eNOS) phosphorylation, and reduces apoptosis. Silencing Fis1 accelerates the switching to STX17-mediated mitophagy, worsening endothelial dysfunction, whereas Fis1 overexpression prevents this switching, reducing ROS and apoptosis and enhancing eNOS phosphorylation. In summary, these findings suggest that the switching from Parkin-mediated to STX17-mediated mitophagy drives vascular endothelial injury following long-term hyperglycemic exposure, providing valuable insights into therapeutic strategies for diabetic cardiovascular complications.

Keywords:  (diabetes; Fis1; Syntaxin 17); mitophagy; vascular endothelial injury

DOI:  https://doi.org/10.1002/advs.202414960
Diabetes. 2025 Mar 28. pii: db240370. [Epub ahead of print]

DA-1241, a GPR119 agonist, ameliorates fatty liver through the upregulation of TFEB-mediated autophagy.

Jin Yoo, Ji Eun Jun, In-Kyung Jeong, Kyu Jeung Ahn, Ho Yeon Chung, Myung-Shik Lee, You-Cheol Hwang.

G protein-coupled receptor 119 (GPR119) is predominantly expressed in pancreatic β-cells, enteroendocrine cells, and the liver. It is a novel therapeutic for dyslipidemia and type 2 diabetes. DA-1241, a GPR119 agonist, improves glucose tolerance by inhibiting gluconeogenesis and enhancing insulin secretion. It mitigates hepatic inflammation by inhibiting NFĸB signaling. However, the mechanism by which DA-1241 ameliorates nonalcoholic fatty liver disease (NAFLD) remains unknown. We hypothesized that DA-1241 improves liver steatosis by inducing autophagy in a TFEB-dependent manner. It induced autophagy and TFEB nuclear translocation, and decreased lipid content in liver cell lines. Lysotracker staining and DQ-Red BSA assay revealed it increased lysosomal activity. Furthermore, DA-1241 increased the colocalization of mRFP-LC3 and lipid droplets, which were completely abolished by GPR119 knockdown. DA-1241 treatment improved glucose tolerance and insulin sensitivity, and decreased liver enzymes activity and hepatic triglyceride levels, and the NAFLD activity score with increased number of autophagosomes and lysosomes in high-fat diet-fed mice. Despite DA-1241 treatment, lysosomal activity and subsequent lipid content reduction were not induced in tfeb knockout HeLa cells. DA-1241 treatment failed to produce favorable metabolic effects, including reduced hepatic triglyceride levels, in liver-specific Tfeb knockout mice. Thus, DA-1241 attenuates hepatic steatosis through TFEB-mediated autophagy induction.

DOI: https://doi.org/10.2337/db24-0370
Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2426929122

Lysosomal PIP3 revealed by genetically encoded lipid biosensors.

Ayse Z Sahan, Mingyuan Chen, Qi Su, Qingrong Li, Dong Wang, Jin Zhang.

  3-Phosphoinositides (3-PIs), phosphatidylinositol (3,4) bisphosphate [PI(3,4)P2] and phosphatidylinositol (3,4,5) trisphosphate (PIP3), are important lipid second messengers in the Phosphoinositide 3-Kinase (PI3K)/Akt signaling pathway, which is crucial to cell growth and frequently dysregulated in cancer. Emerging evidence suggests these lipid second messengers may be present in membranes beyond the plasma membrane, yet their spatial regulation within other membrane compartments is not well understood. To dissect the spatial regulation of specific 3-PI species, we developed genetically encodable biosensors with selectivity for PIP3 or PI(3,4)P2. Using these biosensors, we showed that PIP3 significantly accumulated at the lysosome upon growth factor stimulation, in contrast to the conventional view that PIP3 is exclusively present in the plasma membrane. Furthermore, we showed that lysosomal PIP3 originates from the plasma membrane and relies on dynamin-dependent endocytosis for lipid internalization. Thus, PIP3 can exploit dynamic trafficking pathways to access subcellular compartments and regulate signaling in a spatially selective manner.

Keywords:  3-phosphoinositide; cellular signaling; fluorescent biosensor; lysosome; spatiotemporal regulation

DOI:  https://doi.org/10.1073/pnas.2426929122
Life (Basel). 2025 Feb 26. pii: 368. [Epub ahead of print]15(3):

Tuberous Sclerosis Complex: New Insights into Pathogenesis and Therapeutic Breakthroughs.

Aurora Alexandra Jurca, Alexandru Daniel Jurca, Codruta Diana Petchesi, Dan Bembea, Claudia Maria Jurca, Emilia Severin, Sanziana Jurca, Cosmin Mihai Vesa.

  Background/Objectives: Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disorder caused by mutations in the TSC1 and TSC2 genes, which disrupt the regulation of the mammalian target of rapamycin (mTOR) pathway, a critical regulator of cellular growth. The disorder presents as a multisystem condition, with benign tumors (hamartomas) developing in organs such as the brain, skin, heart, kidneys, and lungs, leading to significant clinical variability and impact on quality of life. This review aims to summarize recent advances in the understanding of TSC pathogenesis and clinical variability and evaluate the therapeutic breakthroughs in targeted treatments. Methods: A narrative review was conducted using various available databases. We applied objective evaluation metrics, such as the impact factor of the journals and the citation count, to assess the quality of the studies. Results: Targeted therapies, particularly mTOR inhibitors (mTORis), have shown efficacy in reducing hamartoma size, improving neuropsychiatric symptoms, and enhancing patient outcomes. Despite these advances, variability in disease expression poses challenges in diagnosis and individualized management strategies. Conclusions: Challenges such as early diagnosis, optimizing long-term outcomes, and addressing residual unmet needs remain critical. Future research should prioritize precision medicine approaches and patient-centered care models within centers of expertise to improve treatment efficacy and quality of life for individuals with TSC.

Keywords:  TSC1 gene; TSC2 gene; hamartomas; mTOR inhibitors

DOI:  https://doi.org/10.3390/life15030368