bims-auttor 2025-01-05 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–01–05
24 papers selected by
Viktor Korolchuk, Newcastle University

ATG9A facilitates the closure of mammalian autophagosomes.
Advances in Aggrephagy: Mechanisms, Disease Implications, and Therapeutic Strategies.
Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survival.
Asparagine endopeptidase regulates lysosome homeostasis via modulating endomembrane phosphoinositide composition.
Deep learning identification of novel autophagic protein-protein interactions and experimental validation of Beclin 2-Ubiquilin 1 axis in triple-negative breast cancer.
Stress granules sequester autophagy proteins to facilitate plant recovery from heat stress.
Deficiency in NPC2 results in disruption of mitochondria-late endosome/lysosomes contact sites and endo-lysosomal lipid dyshomeostasis.
Application of autophagy in mesenchymal stem cells.
mTOR Signaling Regulates Multiple Metabolic Pathways in Human Lung Fibroblasts After TGF-β and in Pulmonary Fibrosis.
Dynamic interplay of autophagy and membrane repair during Mycobacterium tuberculosis Infection.
Ca2+/calmodulin-dependent protein kinase II β decodes ER Ca2+ transients to trigger autophagosome formation.
OSP-1 protects neurons from autophagic cell death induced by acute oxidative stress.
Arginine depletion-induced autophagy and metabolic dysregulation are involved in the disease severity of hand, foot, and mouth disease.
An AMBRA1, ULK1 and PP2A regulatory network regulates cytotoxic T cell differentiation via TFEB activation.
G-cleave LC3B biosensor: monitoring autophagy and assessing resveratrol's synergistic impact on doxorubicin-induced apoptosis in breast cancer cells.
NS1 binding protein regulates stress granule dynamics and clearance by inhibiting p62 ubiquitination.
LncRNA Tug1 Regulates Post-Stroke Microglial Pyroptosis via PINK1/Parkin-Mediated Mitophagy.
Nuclear receptor 4A1 Regulates Mitochondrial Homeostasis in Cardiac Post-Ischemic Injury by Controlling Mitochondrial Fission 1 Protein-Mediated Fragmentation and Parkin-Dependent Mitophagy.
MYO18B promotes lysosomal exocytosis by facilitating focal adhesion maturation.
Mechanical compressive forces increase PI3K output signaling in breast and pancreatic cancer cells.
Fuzhisan ameliorates cognitive ability in Alzheimer's disease by p62 and related autophagy regulatory pathways.
Dysregulation of mTOR signalling is a converging mechanism in lissencephaly.
Hypoxia-induced TPC2 transcription and glycosylation aggravates pulmonary arterial hypertension by blocking autophagy flux.
Omentin-1 mitigates non-alcoholic fatty liver disease by preserving autophagy through AMPKα/mTOR signaling pathway.

J Cell Biol. 2025 Feb 03. pii: e202404047. [Epub ahead of print]224(2):

ATG9A facilitates the closure of mammalian autophagosomes.

Ruheena Javed, Muriel Mari, Einar Trosdal, Thabata Duque, Masroor Ahmad Paddar, Lee Allers, Michal H Mudd, Aurore Claude-Taupin, Prithvi Reddy Akepati, Emily Hendrix, Yi He, Michelle Salemi, Brett Phinney, Yasuo Uchiyama, Fulvio Reggiori, Vojo Deretic.

Canonical autophagy captures within specialized double-membrane organelles, termed autophagosomes, an array of cytoplasmic components destined for lysosomal degradation. An autophagosome is completed when the growing phagophore undergoes ESCRT-dependent membrane closure, a prerequisite for its subsequent fusion with endolysosomal organelles and degradation of the sequestered cargo. ATG9A, a key integral membrane protein of the autophagy pathway, is best known for its role in the formation and expansion of phagophores. Here, we report a hitherto unappreciated function of mammalian ATG9A in directing autophagosome closure. ATG9A partners with IQGAP1 and key ESCRT-III component CHMP2A to facilitate this final stage in autophagosome formation. Thus, ATG9A is a central hub governing all major aspects of autophagosome membrane biogenesis, from phagophore formation to its closure, and is a unique ATG factor with progressive functionalities affecting the physiological outputs of autophagy.

DOI: https://doi.org/10.1083/jcb.202404047
J Cell Physiol. 2025 Jan;240(1): e31512

Advances in Aggrephagy: Mechanisms, Disease Implications, and Therapeutic Strategies.

Haixia Zhuang, Xinyu Ma.

  The accumulation of misfolded proteins within cells leads to the formation of protein aggregates that disrupt normal cellular functions and contribute to a range of human pathologies, notably neurodegenerative disorders. Consequently, the investigation into the mechanisms of aggregate formation and their subsequent clearance is of considerable importance for the development of therapeutic strategies. The clearance of protein aggregates is predominantly achieved via the autophagy-lysosomal pathway, a process known as aggrephagy. In this pathway, autophagosome biogenesis and lysosomal digestion provide necessary conditions for the clearance of protein aggregates, while autophagy receptors such as P62, NBR1, TAX1BP1, TOLLIP, and CCT2 facilitate the recognition of protein aggregates by the autophagy machinery, playing a pivotal role in their degradation. This review will introduce the mechanisms of aggregate formation, progression, and degradation, with particular emphasis on advances in aggrephagy, providing insights for aggregates-related diseases and the development of novel therapeutic strategies.

Keywords:  aggrephagy; aggrephagy receptors; autophagy; neurodegeneration; protein aggregates

DOI:  https://doi.org/10.1002/jcp.31512
Autophagy. 2025 Jan 02. 1-21

Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survival.

Laura Zein, Marvin Dietrich, Denise Balta, Verian Bader, Christoph Scheuer, Suzanne Zellner, Nadine Weinelt, Julia Vandrey, Muriel C Mari, Christian Behrends, Friederike Zunke, Konstanze F Winklhofer, Sjoerd J L Van Wijk.

  Lysosomes are the major cellular organelles responsible for nutrient recycling and degradation of cellular material. Maintenance of lysosomal integrity is essential for cellular homeostasis and lysosomal membrane permeabilization (LMP) sensitizes toward cell death. Damaged lysosomes are repaired or degraded via lysophagy, during which glycans, exposed on ruptured lysosomal membranes, are recognized by galectins leading to K48- and K63-linked poly-ubiquitination (poly-Ub) of lysosomal proteins followed by recruitment of the macroautophagic/autophagic machinery and degradation. Linear (M1) poly-Ub, catalyzed by the linear ubiquitin chain assembly complex (LUBAC) E3 ligase and removed by OTULIN (OTU deubiquitinase with linear linkage specificity) exerts important functions in immune signaling and cell survival, but the role of M1 poly-Ub in lysosomal homeostasis remains unexplored. Here, we demonstrate that L-leucyl-leucine methyl ester (LLOMe)-damaged lysosomes accumulate M1 poly-Ub in an OTULIN- and K63 Ub-dependent manner. LMP-induced M1 poly-Ub at damaged lysosomes contributes to lysosome degradation, recruits the NFKB (nuclear factor kappa B) modulator IKBKG/NEMO and locally activates the inhibitor of NFKB kinase (IKK) complex to trigger NFKB activation. Inhibition of lysosomal degradation enhances LMP- and OTULIN-regulated cell death, indicating pro-survival functions of M1 poly-Ub during LMP and potentially lysophagy. Finally, we demonstrate that M1 poly-Ub also occurs at damaged lysosomes in primary mouse neurons and induced pluripotent stem cell-derived primary human dopaminergic neurons. Our results reveal novel functions of M1 poly-Ub during lysosomal homeostasis, LMP and degradation of damaged lysosomes, with important implications for NFKB signaling, inflammation and cell death.Abbreviation: ATG: autophagy related; BafA1: bafilomycin A1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CRISPR: clustered regularly interspaced short palindromic repeats; CHUK/IKKA: component of inhibitor of nuclear factor kappa B kinase complex; CUL4A-DDB1-WDFY1: cullin 4A-damage specific DNA binding protein 1-WD repeat and FYVE domain containing 1; DGCs: degradative compartments; DIV: days in vitro; DUB: deubiquitinase/deubiquitinating enzyme; ELDR: endo-lysosomal damage response; ESCRT: endosomal sorting complex required for transport; FBXO27: F-box protein 27; GBM: glioblastoma multiforme; IKBKB/IKKB: inhibitor of nuclear factor kappa B kinase subunit beta; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; IKK: inhibitor of NFKB kinase; iPSC: induced pluripotent stem cell; KBTBD7: kelch repeat and BTB domain containing 7; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LCD: lysosomal cell death; LGALS: galectin; LMP: lysosomal membrane permeabilization; LLOMe: L-leucyl-leucine methyl ester; LOP: loperamide; LUBAC: linear ubiquitin chain assembly complex; LRSAM1: leucine rich repeat and sterile alpha motif containing 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NBR1: NBR1 autophagy cargo receptor; NFKB/NF-κB: nuclear factor kappa B; NFKBIA/IĸBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; OPTN: optineurin; ORAS: OTULIN-related autoinflammatory syndrome; OTULIN: OTU deubiquitinase with linear linkage specificity; RING: really interesting new gene; RBR: RING-in-between-RING; PLAA: phospholipase A2 activating protein; RBCK1/HOIL-1: RANBP2-type and C3HC4-type zinc finger containing 1; RNF31/HOIP: ring finger protein 31; SHARPIN: SHANK associated RH domain interactor; SQSTM1/p62: sequestosome 1; SR-SIM: super-resolution-structured illumination microscopy; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TH: tyrosine hydroxylase; TNF/TNFα: tumor necrosis factor; TNFRSF1A/TNFR1-SC: TNF receptor superfamily member 1A signaling complex; TRIM16: tripartite motif containing 16; Ub: ubiquitin; UBE2QL1: ubiquitin conjugating enzyme E2 QL1; UBXN6/UBXD1: UBX domain protein 6; VCP/p97: valosin containing protein; WIPI2: WD repeat domain, phosphoinositide interacting 2; YOD1: YOD1 deubiquitinase.

Keywords:  Cell death; LUBAC; NF-κB; OTULIN; linear ubiquitination; lysosomes

DOI:  https://doi.org/10.1080/15548627.2024.2443945
Cell Death Dis. 2025 Jan 02. 15(12): 883

Asparagine endopeptidase regulates lysosome homeostasis via modulating endomembrane phosphoinositide composition.

Linli Yao, GuangHui Zi, Miao He, Yuhong Xu, Lulu Wang, Baowei Peng.

Asparagine endopeptidase (AEP) is ubiquitously expressed in both physiological and pathological contexts, yet its precise role and functional mechanism in breast cancer remain elusive. Here, we identified increased AEP expression in breast cancer tissues, which correlated with poorer survival rates and a propensity for lung metastasis among breast cancer patients. Loss of AEP impaired colony formation by breast cancer cells in vitro and suppressed lung metastasis in mice. By Gene Set Enrichment Analysis (GSEA) analysis, we uncovered a positive association between aberrant AEP expression and autophagy as well as lysosomal function. Loss of AEP in breast cancer cells led to reduced autophagosome clearance and impaired lysosomal degradation. Mechanically, by co-immunoprecipitation and in vitro enzymatic cleavage assays, we identified the regulatory subunit p85 of class IA PI3K phosphatidylinositol 3-kinase (PI3K), as a substrate of AEP. Loss of AEP led to elevated endo/lysosomal PI3K activity and subsequent conversion of PtdIns(4,5)P2 (PIP2) to PtdIns(3,4,5)P3 (PIP3) on endo/lysosome membranes. Notably, the novel function of endo/lysosomal PI3K which was differently with its role in cytomembrane, was revealed by pharmacological inhibition with a potent endo/lysosomal PI3K inhibitor PIK75. PIK75 treatment showed increased vacuolar-ATPase assembly endo/lysosome membranes, prevented over lysosome perinuclear clustering/fusion and enhanced autophagosome clearance. Our findings demonstrate that AEP regulates cellular autophagy by modulating lysosomal function through its control over endo/lysosomal PI3K activity. These results suggest that AEP may serve as a potential target for suppressing metabolic adaptations in cancer.

DOI: https://doi.org/10.1038/s41419-024-07187-3
Oncol Res. 2025 ;33(1): 67-81

Deep learning identification of novel autophagic protein-protein interactions and experimental validation of Beclin 2-Ubiquilin 1 axis in triple-negative breast cancer.

Xiang Li, Wenke Jin, Lifeng Wu, Huan Wang, Xin Xie, Wei Huang, B O Liu.

   Background: Triple-negative breast cancer (TNBC), characterized by its lack of traditional hormone receptors and HER2, presents a significant challenge in oncology due to its poor response to conventional therapies. Autophagy is an important process for maintaining cellular homeostasis, and there are currently autophagy biomarkers that play an effective role in the clinical treatment of tumors. In contrast to targeting protein activity, intervention with protein-protein interaction (PPI) can avoid unrelated crosstalk and regulate the autophagy process with minimal interference pathways.
Methods: Here, we employed Naive Bayes, Decision Tree, and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC, aiming to uncover novel therapeutic targets. Meanwhile, the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay, and the interaction relationship was verified by molecular docking and CO-IP experiments after intersection. Colony formation, cellular immunofluorescence, cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests were used to predict the clinical therapeutic effects of manipulating candidate PPI.
Results: By developing three PPI classification models and analyzing over 13,000 datasets, we identified 3733 previously unknown autophagy-related PPIs. Our network analysis revealed the central role of Beclin 2 in autophagy regulation, uncovering its interactions with 39 newly identified proteins. Notably, the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1, which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay results. Subsequently, in vitro investigations showed that overexpressing Beclin 2 increased Ubiquilin 1, promoted autophagy-dependent cell death, and inhibited proliferation and metastasis in MDA-MB-231 cells.
Conclusions: This study not only enhances our understanding of autophagy regulation in TNBC but also identifies the Beclin 2-Ubiquilin 1 axis as a promising target for precision therapy. These findings open new avenues for drug discovery and offer inspiration for more effective treatments for this aggressive cancer subtype.

Keywords:  Artificial intelligence (AI); Autophagy; Beclin 2; Protein-protein interactions (PPI); Triple-negative breast cancer (TNBC); Ubiquilin 1

DOI:  https://doi.org/10.32604/or.2024.055921
Nat Commun. 2024 Dec 30. 15(1): 10910

Stress granules sequester autophagy proteins to facilitate plant recovery from heat stress.

Xibao Li, Jun Liao, Ka Kit Chung, Lei Feng, Yanglan Liao, Zhixin Yang, Chuanliang Liu, Jun Zhou, Wenjin Shen, Hongbo Li, Chengwei Yang, Xiaohong Zhuang, Caiji Gao.

The autophagy pathway regulates the degradation of misfolded proteins caused by heat stress (HS) in the cytoplasm, thereby maintaining cellular homeostasis. Although previous studies have established that autophagy (ATG) genes are transcriptionally upregulated in response to HS, the precise regulation of ATG proteins at the subcellular level remains poorly understood. In this study, we provide compelling evidence for the translocation of key autophagy components, including the ATG1/ATG13 kinase complex (ATG1a, ATG13a), PI3K complex (ATG6, VPS34), and ATG8-PE system (ATG5), to HS-induced stress granules (SGs) in Arabidopsis thaliana. As HS subsides, SGs disassemble, leading to the re-translocation of ATG proteins back to the cytoplasm, thereby facilitating the rapid activation of autophagy to degrade HS-induced ubiquitinated aggregates. Notably, autophagy activation is delayed in the SG-deficient (ubp1abc) mutants during the HS recovery phase, resulting in an insufficient clearance of ubiquitinated insoluble proteins that arise due to HS. Collectively, this study uncovers a previously unknown function of SGs in regulating autophagy as a temporary repository for ATG proteins under HS and provides valuable insights into the cellular mechanisms that maintain protein homeostasis during stress.

DOI: https://doi.org/10.1038/s41467-024-55292-w
Sci Rep. 2025 Jan 02. 15(1): 325

Deficiency in NPC2 results in disruption of mitochondria-late endosome/lysosomes contact sites and endo-lysosomal lipid dyshomeostasis.

Raffaele Pastore, Lihang Yao, Nathan Hatcher, Martin Helley, Janet Brownlees, Radha Desai.

Dysfunction of the endo-lysosomal intracellular Cholesterol transporter 2 protein (NPC2) leads to the onset of Niemann-Pick Disease Type C (NPC), a lysosomal storage disorder. Metabolic and homeostatic mechanisms are disrupted in lysosomal storage disorders (LSDs) hence we characterized a cellular model of NPC2 knock out, to assess alterations in organellar function and inter-organellar crosstalk between mitochondria and lysosomes. We performed characterization of lipid alterations and confirmed altered lysosomal morphology, but no overt changes in oxidative stress markers. Using several techniques, we demonstrated that contacts between mitochondria and late endosomes/lysosomes are reduced in NPC2-/- HEK cells, we observed that the acidic compartments are swollen and lipid dense. Quantification of endogenous lipids in HEKNPC2-/- cells by mass spectrometry reveals accumulation of lipid species indicative of sphingolipid metabolic dysregulation within the lysosome. Specifically, HEK NPC2-/- cells exhibit marked elevation of glucosylsphingosine and glucosylceramides, substrates of beta glucocerebroside (GBA), as well as accumulation of sphingosine and sphingomyelins. Our studies suggest an involvement of NPC2 in the formation of contact sites between mitochondria and lysosomes and support the hypothesis of a role for NPC2 in the endo-lysosomal trafficking pathway and dynamic organellar crosstalk.

DOI: https://doi.org/10.1038/s41598-024-83460-x
World J Stem Cells. 2024 Dec 26. 16(12): 990-1001

Application of autophagy in mesenchymal stem cells.

Min Chai, Chun-Yan Zhang, Shuai Chen, Da-Hai Xu.

  In this editorial, we have taken an in-depth look at the article published by Wan et al. The study showed that preconditioning mesenchymal stem cells (MSCs) protected them against programmed cell death, and increased their survival rate and therapeutic potential. Autophagy, a type of programmed cell death, is a major intracellular degradation and recycling pathway that is crucial for maintaining cellular homeostasis, self-renewal, and pluripotency. We have explored the relationship between autophagy and MSCs to determine the role of autophagy in the therapeutic applications of MSCs.

Keywords:  Apoptosis; Autophagy; Bone marrow mesenchymal stem cells; Mesenchymal stem cells; Programmed cell death; Umbilical cord mesenchymal stem cells

DOI:  https://doi.org/10.4252/wjsc.v16.i12.990
Am J Physiol Lung Cell Mol Physiol. 2025 Jan 02.

mTOR Signaling Regulates Multiple Metabolic Pathways in Human Lung Fibroblasts After TGF-β and in Pulmonary Fibrosis.

Kun Woo D Shin, M Volkan Atalay, Rengul Cetin-Atalay, Erin M O'Leary, Mariel E Glass, Jennifer C Houpy Szafran, Parker S Woods, Angelo Y Meliton, Obada R Shamaa, Yufeng Tian, Gökhan M Mutlu, Robert B Hamanaka.

  Idiopathic pulmonary fibrosis is a fatal disease characterized by the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive replacement of healthy lung with scar tissue. We and others have shown that TGF-β-mediated activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and downstream upregulation of Activating Transcription Factor 4 (ATF4) promote metabolic reprogramming in lung fibroblasts characterized by upregulation of the de novo synthesis of glycine, the most abundant amino acid found in collagen protein. Whether mTOR and ATF4 regulate other metabolic pathways in lung fibroblasts has not been explored. Here, we used RNA sequencing to determine how both ATF4 and mTOR regulate gene expression in human lung fibroblasts following TGF-β. We found that ATF4 primarily regulates enzymes and transporters involved in amino acid homeostasis as well as aminoacyl-tRNA synthetases. mTOR inhibition resulted not only in the loss of ATF4 target gene expression, but also in the reduced expression of glycolytic enzymes and mitochondrial electron transport chain subunits. Analysis of TGF-β-induced changes in cellular metabolite levels confirmed that ATF4 regulates amino acid homeostasis in lung fibroblasts while mTOR also regulates glycolytic and TCA cycle metabolites. We further analyzed publicly available single-cell RNA-seq data sets and found increased expression of ATF4 and mTOR-regulated genes in pathologic fibroblast populations from the lungs of IPF patients. Our results provide insight into the mechanisms of metabolic reprogramming in lung fibroblasts and highlight novel ATF4 and mTOR-dependent pathways that may be targeted to inhibit fibrotic processes.

Keywords:  ATF4; Fibrosis; Metabolism; mTOR

DOI:  https://doi.org/10.1152/ajplung.00189.2024
PLoS Pathog. 2025 Jan 02. 21(1): e1012830

Dynamic interplay of autophagy and membrane repair during Mycobacterium tuberculosis Infection.

Jacques Augenstreich, Anna T Phan, Charles N S Allen, Anushka Poddar, Hanzhang Chen, Lalitha Srinivasan, Volker Briken.

Autophagy plays a crucial role in the host response to Mycobacterium tuberculosis (Mtb) infection, yet the dynamics and regulation of autophagy induction on Mtb-containing vacuoles (MCVs) remain only partially understood. We employed time-lapse confocal microscopy to investigate the recruitment of LC3B (LC3), a key autophagy marker, to MCVs at the single cell level with our newly developed workflow for single cell and single MCV tracking and fluorescence quantification. We show that approximately 70% of MCVs exhibited LC3 recruitment but that was lost in about 40% of those MCVs. The LC3 recruitment to MCVs displayed a high variability in timing that was independent of the size of the MCV or the bacterial burden. Most notably, the LC3-positive MCVs did not acidify, indicating that LC3 recruitment does not necessarily lead to the formation of mature autophagolysosomes. Interferon-gamma pre-treatment did not affect LC3 recruitment frequency or autophagosome acidification but increased the susceptibility of the macrophage to Mtb-induced cell death. LC3 recruitment and lysotracker staining were mutually exclusive events, alternating on some MCVs multiple times thus demonstrating a reversible aspect of the autophagy response. The LC3 recruitment was associated with galectin-3 and oxysterol-binding protein 1 staining, indicating a correlation with membrane damage and repair mechanisms. ATG7 knock-down did not impact membrane repair, suggesting that autophagy is not directly involved in this process but is coregulated by the membrane damage of MCVs. In summary, our findings provide novel insights into the dynamic and variable nature of LC3 recruitment to the MCVs over time during Mtb infection. Our data does not support a role for autophagy in either cell-autonomous defense against Mtb or membrane repair of the MCV in human macrophages. In addition, the combined dynamics of LC3 recruitment and Lysoview staining emerged as promising markers for investigating the damage and repair processes of phagosomal membranes.

DOI: https://doi.org/10.1371/journal.ppat.1012830
Mol Cell. 2024 Dec 26. pii: S1097-2765(24)01000-1. [Epub ahead of print]

Ca2+/calmodulin-dependent protein kinase II β decodes ER Ca2+ transients to trigger autophagosome formation.

Qiaoxia Zheng, Huan Zhang, Hongyu Zhao, Yong Chen, Hongzhining Yang, Tingting Li, Qixu Cai, Yingyu Chen, Youjun Wang, Mingjie Zhang, Hong Zhang.

  In multicellular organisms, very little is known about how Ca2+ transients on the ER outer surface elicited by autophagy stimuli are sustained and decoded to trigger autophagosome formation. Here, we show that Ca2+/calmodulin-dependent protein kinase II β (CaMKIIβ) integrates ER Ca2+ transients to trigger liquid-liquid phase separation (LLPS) of the autophagosome-initiating FIP200 complex. In response to ER Ca2+ transients, CaMKIIβ is recruited from actin filaments and forms condensates, which serve as sites for the emergence of or interaction with FIP200 puncta. CaMKIIβ phosphorylates FIP200 at Thr269, Thr1127, and Ser1484 to modulate LLPS and properties of the FIP200 complex, thereby controlling its function in autophagosome formation. CaMKIIβ also controls the amplitude, duration, and propagation of ER Ca2+ transients during autophagy induction. CaMKIIβ mutations identified in the neurodevelopmental disorder MRD54 affect the function of CaMKIIβ in autophagy. Our study reveals that CaMKIIβ is essential for sustaining and decoding ER Ca2+ transients to specify autophagosome formation in mammalian cells.

Keywords:  Ca(2+) transient; CaMKIIβ; FIP200; autophagosome; liquid-liquid phase separation

DOI:  https://doi.org/10.1016/j.molcel.2024.12.005
Nat Commun. 2025 Jan 02. 16(1): 300

OSP-1 protects neurons from autophagic cell death induced by acute oxidative stress.

Alessandra Donato, Fiona K Ritchie, Lachlan Lu, Mehershad Wadia, Ramon Martinez-Marmol, Eva Kaulich, Kornraviya Sankorrakul, Hang Lu, Sean Coakley, Elizabeth J Coulson, Massimo A Hilliard.

Oxidative stress, caused by the accumulation of reactive oxygen species (ROS), is a pathological factor in several incurable neurodegenerative conditions as well as in stroke. However, our knowledge of the genetic elements that can be manipulated to protect neurons from oxidative stress-induced cell death is still very limited. Here, using Caenorhabditis elegans as a model system, combined with the optogenetic tool KillerRed to spatially and temporally control ROS generation, we identify a previously uncharacterized gene, oxidative stress protective 1 (osp-1), that protects C. elegans neurons from oxidative damage. Using rodent and human cell cultures, we also show that the protective effect of OSP-1 extends to mammalian cells. Moreover, we demonstrate that OSP-1 functions in a strictly cell-autonomous fashion, and that it localizes to the endoplasmic reticulum (ER) where it has an ER-remodeling function. Finally, we present evidence suggesting that OSP-1 may exert its neuroprotective function by influencing autophagy. Our results point to a potential role of OSP-1 in modulating autophagy, and suggest that overactivation of this cellular process could contribute to neuronal death triggered by oxidative damage.

DOI: https://doi.org/10.1038/s41467-024-55105-0
Virulence. 2025 Dec;16(1): 2440541

Arginine depletion-induced autophagy and metabolic dysregulation are involved in the disease severity of hand, foot, and mouth disease.

Yuefei Jin, Wangquan Ji, Liang Zhang, Dejian Dang, Bingqing Yu, Xiaolong Zhang, Yuxiang Zhang, Jiaqi Li, Yaodong Zhang, Rongxin Yang, Haiyan Yang, Shuaiyin Chen, Fang Wang, Guangcai Duan.

  Amino acid metabolism provides significant insight into the development and prevention of many viral diseases. Therefore, the present study aimed to compare the amino acid profiles of hand, foot, and mouth disease (HFMD) patients with those of healthy individuals and to further reveal the molecular mechanisms of HFMD severity. Using UPLC-MS/MS, we determined the plasma amino acid expression profiles of pediatric patients with HFMD (mild, n = 42; severe, n = 43) and healthy controls (n = 25). Brain tissues from CVA6-infected mice were examined using untargeted metabolomics. Several amino acids were significantly different between the three groups. Pathway analysis revealed that arginine, proline, and tryptophan metabolism are implicated in the pathogenesis of HFMD. A similar arginine depletion was observed in the brain tissues of CVA6-infected mice. Importantly, L-arginine supplementation improved the survival rate of CVA6-infected mice, inhibited virus multiplication, and reduced pathological autophagy associated with mTOR-autophagy pathway in the brain. Collectively, arginine, as the hub amino acid metabolite of the mammalian target of rapamycin (mTOR) signaling pathway affecting autophagy, plays an important role in the pathogenesis of severe HFMD. L-arginine supplementation may serve as a potential therapeutic option for critical patients with HFMD.

Keywords:  CVA6; Hand, foot, and mouth disease; arginine; autophagy; mTOR

DOI:  https://doi.org/10.1080/21505594.2024.2440541
Sci Rep. 2024 Dec 30. 14(1): 31838

An AMBRA1, ULK1 and PP2A regulatory network regulates cytotoxic T cell differentiation via TFEB activation.

Loredana Migliore, Valentina Cianfanelli, Fabrizia Zevolini, Monica Gesualdo, Leandro Marzuoli, Laura Patrussi, Cristina Ulivieri, Giuseppe Marotta, Francesco Cecconi, Francesca Finetti, Cosima T Baldari.

  The scaffold protein AMBRA1, which participates in the autophagy pathway, also promotes CD4+ T cell differentiation to Tregs independent of autophagy through its interactor PP2A. Here we have investigated the role of AMBRA1 in CD8+ T cell differentiation to cytotoxic T cells (CTL). AMBRA1 depletion in CD8+ T cells was associated with impaired expression of the transcription factors RUNX3 and T-BET that drive CTL differentiation and resulted in impaired acquisition of cytotoxic potential. These effects were recapitulated by pharmacological inhibition of the AMBRA1 activator ULK1 or its interactor PP2A. Based on the ability of PP2A to activate TFEB, we hypothesized a role for TFEB in the CTL differentiation program regulated by AMBRA1. We show that TFEB modulates RUNX3 and T-BET expression and the generation of killing-competent CTLs, and that AMBRA1 depletion, or ULK1 or PP2A inhibition, suppresses TFEB activity. These data highlight a role for AMBRA1, ULK1 and PP2A in CTL generation, mediated by TFEB, which we identify as a new pioneering transcription factor in the CTL differentiation program.

Keywords:  AMBRA1; Cytotoxic T cell; Lytic granule /; PP2A / ULK1

DOI:  https://doi.org/10.1038/s41598-024-82957-9
Breast Cancer Res. 2024 Dec 30. 26(1): 190

G-cleave LC3B biosensor: monitoring autophagy and assessing resveratrol's synergistic impact on doxorubicin-induced apoptosis in breast cancer cells.

Chiao-Chun Liao, Yuqing Long, Ming-Lin Tsai, Chun-Yu Lin, Kai-Wen Hsu, Chia-Hwa Lee.

  Autophagy, a crucial process in cancer, is closely intertwined with both tumor progression and drug resistance development. However, existing methods used to assess autophagy activity often pose invasiveness and time-related constraints, limiting their applicability in preclinical drug investigations. In this study, we developed a non-invasive autophagy detection system (NIADS-autophagy, also called G-cleave LC3B biosensor) by integrating a split-luciferase-based biosensor with an LC3B cleavage sequence, which swiftly identified classic autophagic triggers, such as Earle's Balanced Salt Solution and serum deprivation, through protease-mediated degradation pathways. The specificity of G-cleave LC3B biosensor was confirmed via CRISPR gene editing of pivotal autophagy regulator ATG4B, yielding diminished luciferase activity in MDA-MB-231 breast cancer cells. Notably, the G-cleave LC3B biosensor exhibited strong concordance with established autophagy metrics, encompassing LC3B lipidation, SQSTM1 degradation, and puncta accumulation analysis. To underscore the usage potential of the G-cleave LC3B biosensor, we discovered that resveratrol acts as a synergistic enhancer by significantly potentiating apoptosis in MDA-MB-231 cells when combined with doxorubicin treatment. Overall, the luminescence-based G-cleave LC3B biosensor presents a rapid and dependable avenue for determining autophagy activity, thereby facilitating high-throughput assessment of promising autophagy-associated anti-cancer therapies across diverse malignancies.

Keywords:  Autophagy; Breast cancer; Doxorubicin; G-cleave LC3B biosensor; Non-invasive autophagy detection system (NIADS); Resveratrol

DOI:  https://doi.org/10.1186/s13058-024-01951-1
Nat Commun. 2024 Dec 30. 15(1): 10925

NS1 binding protein regulates stress granule dynamics and clearance by inhibiting p62 ubiquitination.

Pureum Jeon, Hyun-Ji Ham, Haneul Choi, Semin Park, Jae-Woo Jang, Sang-Won Park, Dong-Hyung Cho, Hyun-Jeong Lee, Hyun Kyu Song, Masaaki Komatsu, Dohyun Han, Deok-Jin Jang, Jin-A Lee.

The NS1 binding protein, known for interacting with the influenza A virus protein, is involved in RNA processing, cancer, and nerve cell growth regulation. However, its role in stress response independent of viral infections remains unclear. This study investigates NS1 binding protein's function in regulating stress granules during oxidative stress through interactions with GABARAP subfamily proteins. We find that NS1 binding protein localizes to stress granules, interacting with core components, GABARAP proteins, and p62, a protein involved in autophagy. In cells lacking NS1 binding protein, stress granule dynamics are altered, and p62 ubiquitination is increased, suggesting impaired stress granule degradation. Overexpression of NS1 binding protein reduces p62 ubiquitination. In amyotrophic lateral sclerosis patient-derived neurons, reduced NS1 binding protein and p62 disrupt stress granule morphology. These findings identify NS1 binding protein as a negative regulator of p62 ubiquitination and a facilitator of GABARAP recruitment to stress granules, implicating it in stress granule regulation and amyotrophic lateral sclerosis pathogenesis.

DOI: https://doi.org/10.1038/s41467-024-55446-w
Inflammation. 2024 Dec 30.

LncRNA Tug1 Regulates Post-Stroke Microglial Pyroptosis via PINK1/Parkin-Mediated Mitophagy.

Meiling Yao, Xiaobei Wang, Hao Lin, Hui Shu, Zongtang Xu, Ling Tang, Wenyuan Guo, Pingyi Xu.

  Microglia, the central nervous system's primary immune cells, play a key role in the progression of cerebral ischemic stroke, particularly through their involvement in pyroptosis. The long non-coding RNA taurine up-regulated gene 1 (Tug1) is elevated during ischemic stroke and is critical in driving post-stroke neuroinflammation. However, the underlying molecular mechanisms remain unclear. This study explores the biological role of Tug1 and its potential mechanisms in regulating pyroptosis in microglia. We utilized an in vivo photothrombosis (PT) mice model and an in vitro oxygen-glucose deprivation and reperfusion (OGD/R) BV2 cell model to explore the mechanisms underlying ischemic stroke. Initially, we assessed the expression levels of Tug1 in the OGD/R model in vitro and the PT model in vivo. Subsequently, we investigated the impact of Tug1 on microglial pyroptosis by knocking down Tug1, silencing the PTEN-induced putative kinase 1 (Pink1) expression, and employing the mitophagy inhibitor mdivi-1. Tug1 exacerbated microglial pyroptosis by inhibiting mitophagy in both in vivo and in vitro models. The increase in mitophagy observed following Tug1 knockdown was reversed by either silencing Pink1 expression or using the mitophagy inhibitor mdivi-1. This reversal resulted in exacerbated pyroptosis and worsened neurological damage. Further mechanistic studies revealed that Tug1 knockdown significantly reduced microglial pyroptosis and alleviated neuronal damage by enhancing PINK1/Parkin-mediated mitophagy. For the first time, this study reveals that Tug1 promotes hypoxia-induced microglial pyroptosis by inhibiting PINK1/Parkin-mediated mitophagy, potentially providing a promising therapeutic target for ischemic inflammatory injury.

Keywords:  Autophagy; Ischemic Stroke; LncRNA Tug1 ; Pyroptosis

DOI:  https://doi.org/10.1007/s10753-024-02219-8
Int J Biol Sci. 2025 ;21(1): 400-414

Nuclear receptor 4A1 Regulates Mitochondrial Homeostasis in Cardiac Post-Ischemic Injury by Controlling Mitochondrial Fission 1 Protein-Mediated Fragmentation and Parkin-Dependent Mitophagy.

Haoran Ye, Jialong Lin, Hui Zhang, Jing Wang, Yuan Fu, Zhaopei Zeng, Junmeng Zheng, Jun Tao, Junxiong Qiu.

  The close interaction of mitochondrial fission and mitophagy, two crucial mechanisms, is key in the progression of myocardial ischemia-reperfusion (IR) injury. However, the upstream regulatory mechanisms governing these processes remain poorly understood. Here, we demonstrate a marked elevation in Nr4a1 expression following myocardial IR injury, which is associated with impaired cardiac function, heightened cardiomyocyte apoptosis, exacerbated inflammatory responses, and endothelial dysfunction. Notably, Nr4a1-knockout mice exhibited remarkable resistance to acute myocardial IR injury, characterized by preserved mitochondrial integrity relative to their wild-type counterparts. Functional analyses revealed that elevated Nr4a1 expression after IR injury promotes Fis1-mediated mitochondrial fission while suppressing Parkin-driven mitophagy. Importantly, interventions that inhibit mitochondrial fission or enhance mitophagy effectively ameliorated IR-induced cardiomyocyte and endothelial dysfunction. Collectively, these results highlight that the absence of Nr4a1 provides a shield against cardiac post-ischemic damage by reinstating balance within the mitochondria through inhibiting Fis1-induced fission and promoting Parkin-triggered mitophagy. Furthermore, therapeutic strategies targeting the Nr4a1/mitochondria axis may offer promising avenues for improving cardiac outcomes under myocardial IR stress.

Keywords:  Cardiac post-ischemic damage; Fis1; Mitochondrial fission and Mitophagy; Nr4a1; Parkin

DOI:  https://doi.org/10.7150/ijbs.104680
J Cell Biol. 2025 Mar 03. pii: e202407068. [Epub ahead of print]224(3):

MYO18B promotes lysosomal exocytosis by facilitating focal adhesion maturation.

Wei-Wei Ren, Rebeca Kawahara, Kenichi G N Suzuki, Priya Dipta, Ganglong Yang, Morten Thaysen-Andersen, Morihisa Fujita.

Many cancer cells exhibit increased amounts of paucimannose glycans, which are truncated N-glycan structures rarely found in mammals. Paucimannosidic proteins are proposedly generated within lysosomes and exposed on the cell surface through a yet uncertain mechanism. In this study, we revealed that paucimannosidic proteins are produced by lysosomal glycosidases and secreted via lysosomal exocytosis. Interestingly, lysosomal exocytosis preferentially occurred in the vicinity of focal adhesions, protein complexes connecting the actin cytoskeleton to the extracellular matrix. Through genome-wide knockout screening, we identified that MYO18B, an actin crosslinker, is required for focal adhesion maturation, facilitating lysosomal exocytosis and the release of paucimannosidic lysosomal proteins to the extracellular milieu. Moreover, a mechanosensitive cation channel PIEZO1 locally activated at focal adhesions imports Ca2+ necessary for lysosome-plasma membrane fusion. Collectively, our study unveiled an intimate relationship between lysosomal exocytosis and focal adhesion, shedding light on the unexpected interplay between lysosomal activities and cellular mechanosensing.

DOI: https://doi.org/10.1083/jcb.202407068
Life Sci Alliance. 2025 Mar;pii: e202402854. [Epub ahead of print]8(3):

Mechanical compressive forces increase PI3K output signaling in breast and pancreatic cancer cells.

Mickaël Di-Luoffo, Céline Schmitter, Emma C Barrere, Nicole Therville, Maria Chaouki, Romina D'Angelo, Silvia Arcucci, Benoit Thibault, Morgan Delarue, Julie Guillermet-Guibert.

Mechanical stresses, including compression, arise during cancer progression. In solid cancer, especially breast and pancreatic cancers, the rapid tumor growth and the environment remodeling explain their high intensity of compressive forces. However, the sensitivity of compressed cells to targeted therapies remains poorly known. In breast and pancreatic cancer cells, pharmacological PI3K inactivation decreased cell number and induced apoptosis. These effects were accentuated when we applied 2D compression forces in mechanically responsive cells. Compression selectively induced the overexpression of PI3K isoforms and PI3K/AKT pathway activation. Furthermore, transcriptional effects of PI3K inhibition and compression converged to control the expression of an autophagy regulator, GABARAP, whose level was inversely associated with PI3K inhibitor sensitivity under compression. Compression alone blocked autophagy flux in all tested cells, whereas inactivation of basal PI3K activity restored autophagy flux only in mechanically non-responsive compressed cells. This study provides direct evidence for the role of the PI3K/AKT pathway in compression-induced mechanotransduction. PI3K inhibition promotes apoptosis or autophagy, explaining PI3K importance to control cancer cell survival under compression.

DOI: https://doi.org/10.26508/lsa.202402854
Brain Res. 2024 Dec 28. pii: S0006-8993(24)00691-7. [Epub ahead of print] 149436

Fuzhisan ameliorates cognitive ability in Alzheimer's disease by p62 and related autophagy regulatory pathways.

Zhaoxu Zhang, Shuangmei Zhang, Shen Liu, Yang He, Anrong Wang.

   BACKGROUND: Maintaining autophagic homeostasis has been proved to play an important role in Alzheimer's disease.
OBJECT: The aim of this study was to investigate the effect of Fuzhisan(FZS) on autophagic function in Alzheimer's disease and to elucidate its potential mechanism through the P62 regulatory pathways.
METHODS: FZS was extracted by water extraction-rotary evaporation method. The novel object recognition test, morris water maze test and Y maze test were used to observe the cognitive and memory ability of APP/PS1 mice. The effects of FZS on the ultrastructure of mice hippocampus were examined by transmission electron microscopy. Molecular level changes were also further detected, including Aβ deposition, tau hyperphosphorylation, SOD, CAT and autophagy related proteins (p62, Nrf2, keap1, mTOR, LC3II/I, Beclin1, Atgs).
RESULTS: FZS could alleviate memory and cognitive impairment in APP/PS1 mice, increase the autophagic vesicles and organelle abundance in hippocampus. FZS also reduced the levels of Aβ and tau hyperphosphorylation in the hippocampus of model mice, upregulated the levels of SOD, CAT and autophagy related proteins (Nrf2, LC3II/LC3I, Beclin1, Atg7 and Atg12) as well as downregulated the expression of P62, keap1 and p-mTOR/mTOR proteins. Co-Ip results showed that FZS elevated the levels of p62/LC3 and P62-keap1-Nrf2 complex, but decreased the P62 and keap1 association.
CONCLUSION: Our findings indicate that FZS may affect autophagy function and oxidative stress by regulating P62 and related pathways to promote the clearance of Aβ and phosphorylated tau, thereby improving the cognitive ability of AD, which provided a novel perspective for exploring the potential mechanism of FZS upon AD.

Keywords:  Alzheimer’s disease; Autophagy; Fuzhisan (FZS); P62

DOI:  https://doi.org/10.1016/j.brainres.2024.149436
Nature. 2025 Jan 01.

Dysregulation of mTOR signalling is a converging mechanism in lissencephaly.

Ce Zhang, Dan Liang, A Gulhan Ercan-Sencicek, Aybike S Bulut, Joelly Cortes, Iris Q Cheng, Octavian Henegariu, Sayoko Nishimura, Xinyuan Wang, A Buket Peksen, Yutaka Takeo, Caner Caglar, TuKiet T Lam, Merve Nur Koroglu, Anand Narayanan, Francesc Lopez-Giraldez, Danielle F Miyagishima, Ketu Mishra-Gorur, Tanyeri Barak, Katsuhito Yasuno, E Zeynep Erson-Omay, Cengiz Yalcinkaya, Guilin Wang, Shrikant Mane, Hande Kaymakcalan, Aslan Guzel, A Okay Caglayan, Beyhan Tuysuz, Nenad Sestan, Murat Gunel, Angeliki Louvi, Kaya Bilguvar.

Cerebral cortex development in humans is a highly complex and orchestrated process that is under tight genetic regulation. Rare mutations that alter gene expression or function can disrupt the structure of the cerebral cortex, resulting in a range of neurological conditions1. Lissencephaly ('smooth brain') spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability2. However, the molecular mechanisms underlying disease pathogenesis remain unknown. Here we establish hypoactivity of the mTOR pathway as a clinically relevant molecular mechanism in lissencephaly spectrum disorders. We characterized two types of cerebral organoid derived from individuals with genetically distinct lissencephalies with a recessive mutation in p53-induced death domain protein 1 (PIDD1) or a heterozygous chromosome 17p13.3 microdeletion leading to Miller-Dieker lissencephaly syndrome (MDLS). PIDD1-mutant organoids and MDLS organoids recapitulated the thickened cortex typical of human lissencephaly and demonstrated dysregulation of protein translation, metabolism and the mTOR pathway. A brain-selective activator of mTOR complex 1 prevented and reversed cellular and molecular defects in the lissencephaly organoids. Our findings show that a converging molecular mechanism contributes to two genetically distinct lissencephaly spectrum disorders.

DOI: https://doi.org/10.1038/s41586-024-08341-9
Sci Rep. 2024 12 28. 14(1): 31223

Hypoxia-induced TPC2 transcription and glycosylation aggravates pulmonary arterial hypertension by blocking autophagy flux.

Chao Li, Cheng Li, YuFei Jiang, MoFei Liu, ChengYi Yang, JiaXin Lu, YongLiang Jiang.

  Pulmonary arterial hypertension (PAH) is a serious medical condition that causes a failure in the right heart. Two-pore channel 2 (TPC2) is upregulated in PAH, but its roles in PAH remain largely unknown. Our investigation aims at the mechanisms by which TPC2 regulates PAH development. We established an experimental PAH rat model via monocrotaline administration. Human and rat pulmonary arterial smooth muscle cells (PASMCs) were treated hypoxia as in vitro cell PAH models. The thickness of pulmonary arterial wall and obstructive arteriopathy in rats were examined. Autophagy was detected through TEM, and Ca2+ measurement and mRFP-GFP-LC3 transfection. The expression of α-SMA, LC3, p62, TPC2, HIF1α and STT3B were analyzed by qRT-PCR, western blot or IHC staining. The binding of HIF1α to TPC2 promoter was determined by ChIP-qPCR and EMSA assays. TPC2 glycosylation was evaluated by western blot. Transwell assay was applied to analyze cell migration. TPC2 expression was promoted and autophagy was inhibited in PAH rats and hypoxia-treated PASMCs. HIF1α directly bound to the promoter of TPC2, thus transcriptionally activating its expression in PAH rats and hypoxic PASMCs. Knockdown of TPC2 facilitated autophagic flux and repressed PASMC migration. STT3B enhanced TPC2 glycosylation in hypoxic PASMCs. Furthermore, Overexpression of TPC2 suppressed autophagic flux and promoted PASMC migration, but these effects were abrogated by STT3B knockdown or PNGase F, an eraser of N-linked glycans. Suppression of TPC2 enhanced autophagy and alleviated PAH in vivo. HIF1α-induced TPC2 transcription and subsequent STT3B-dependent TPC2 glycosylation inhibit autophagic flux and aggravate PAH. Our study suggests TCP2 as a potential therapeutic target for PAH.

Keywords:  Autophagy; Glycosylation; HIF1α; Pulmonary arterial hypertension; STT3B; TPC2

DOI:  https://doi.org/10.1038/s41598-024-82552-y
Sci Rep. 2024 Dec 28. 14(1): 31464

Omentin-1 mitigates non-alcoholic fatty liver disease by preserving autophagy through AMPKα/mTOR signaling pathway.

Ziqing Huang, Linfei Luo, Zhihua Xiao, Ming Xiong, Zhili Wen.

  Adipose tissue-derived adipokines facilitate inter-organ communication between adipose tissue and other organs. Omentin-1, an adipokine, has been implicated in the regulation of glucose and insulin metabolism. However, limited knowledge exists regarding the regulatory impact of endogenous omentin-1 on hepatic steatosis. C57BL/6J mice were fed with high-fat diet (HFD) for 8 weeks to induce nonalcoholic fatty liver disease (NAFLD), while HepG2 cells were exposed to a 0.1 mM free fatty acid (FFA) mixture for 24 h to induce hepatic steatosis. Both the mice and cells were treated with omentin-1, and the therapeutic effects as well as the underlying molecular mechanisms were investigated. Our data demonstrate that omentin-1 attenuates weight and fat mass gain, preserves glucose homeostasis, normalizes the expression of lipogenesis-related proteins, and alleviates hepatic lipid accumulation in HFD fed mice. Furthermore, omentin-1 normalized AMPKα/mTOR signaling and preserves autophagy in these mice. In vitro, omentin-1 also preserves autophagy and attenuates lipid accumulation by normalizing AMPKα/mTOR signaling in a cell model of FFA treated HepG2 cells. However, inhibition of AMPK with Compound C or AMPKα whole-body knockout reverses the above beneficial effects of omentin-1. The present study demonstrates that omentin-1 exerts a preventive effect on non-alcoholic fatty liver disease (NAFLD) by preserving autophagy through normalizing the AMPKα/mTOR pathway, thereby suggesting its potential as a promising therapeutic agent against NAFLD.

Keywords:  AMPK; Autophagy; Nonalcoholic fatty liver disease; Omentin-1; mTOR

DOI:  https://doi.org/10.1038/s41598-024-83112-0