Autophagy最新文献

{"title":"Mammalian nucleophagy: process and function.","authors":"Fujian Ji, Enyong Dai, Rui Kang, Daniel J Klionsky, Tong Liu, Yu Hu, Daolin Tang, Kun Zhu","doi":"10.1080/15548627.2025.2455158","DOIUrl":"10.1080/15548627.2025.2455158","url":null,"abstract":"<p><p>The nucleus is a highly specialized organelle that houses the cell's genetic material and regulates key cellular activities, including growth, metabolism, protein synthesis, and cell division. Its structure and function are tightly regulated by multiple mechanisms to ensure cellular integrity and genomic stability. Increasing evidence suggests that nucleophagy, a selective form of autophagy that targets nuclear components, plays a critical role in preserving nuclear integrity by clearing dysfunctional nuclear materials such as nuclear proteins (lamins, SIRT1, and histones), DNA-protein crosslinks, micronuclei, and chromatin fragments. Impaired nucleophagy has been implicated in aging and various pathological conditions, including cancer, neurodegeneration, autoimmune disorders, and neurological injury. In this review, we focus on nucleophagy in mammalian cells, discussing its mechanisms, regulation, and cargo selection, as well as evaluating its therapeutic potential in promoting human health and mitigating disease.<b>Abbreviations</b>: 5-FU: 5-fluorouracil; AMPK, AMP-activated protein kinase; ATG, autophagy related; CMA, chaperone-mediated autophagy; DRPLA: dentatorubral-pallidoluysian atrophy; ER, endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; HOPS, homotypic fusion and vacuole protein sorting; LIR: LC3-interacting region; MEFs: mouse embryonic fibroblasts; mRNA: messenger RNA; MTORC1: mechanistic target of rapamycin kinase complex 1; PCa: prostate cancer; PE: phosphatidylethanolamine; PI3K, phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; rRNA: ribosomal RNA; SCI: spinal cord injury; SCLC: small cell lung cancer; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SupraT: supraphysiological levels of testosterone; TOP1cc: TOP1 cleavage complexes.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1396-1412"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-associated mutations in autophagy-related proteins analyzed in yeast and human cells.","authors":"Yuchen Lei, Louise Uoselis, Dimitra Dialynaki, Ying Yang, Michael Lazarou, Daniel J Klionsky","doi":"10.1080/15548627.2025.2471142","DOIUrl":"10.1080/15548627.2025.2471142","url":null,"abstract":"<p><p>Macroautophagy/autophagy is a conserved process among eukaryotes and is essential to maintain cell homeostasis; the dysregulation of autophagy has been linked with multiple human diseases, including cancer. However, not many studies have focused on the cancer-related mutations in ATG (autophagy related) proteins, which are likely to affect the protein function, influence autophagy activity and further contribute to the progression of the disease. In this study, we focused on the four ATG4 isoforms, which have a higher mutation frequency compared with the other core ATG proteins (i.e. those involved in autophagosome formation). We first studied the mutations in conserved residues and characterized one cancer-associated mutation that significantly impairs protein function and autophagy activity. Extending the study, we determined a region around the mutant residue to be essential for protein function, which had yet to be examined in previous studies. In addition, we created a yeast system expressing the human ATG4B protein to study mutations in the residues that are not conserved from human to yeast. Using this yeast model, we identified six cancer-associated mutations affecting autophagy. The effects of these mutations were further tested in mammalian cells using a quadruple <i>ATG4</i> gene knockout cell line. Our study proves the principle of using human disease-associated mutations to study Atg proteins in yeast and generates a yeast tool that is helpful for a rapid screen of mutations to determine the autophagy phenotype, providing a new perspective in studying autophagy and its relation with cancer.<b>Abbreviations:</b> 4KO: <i>ATG4</i> tetra knockout; ATG: autophagy related; BafA1: bafilomycin A₁; GFP: green fluorescent protein; LC3-II: PE-conjugated form of LC3B; ORF: open reading frame; PE: phosphatidylethanolamine; RFP: red fluorescent protein; SEP: superecliptic pHluorin; Ubl: ubiquitin-like; UCEC: uterine corpus endometrial carcinoma.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1456-1472"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial dynamics and quality control regulate proteostasis in neuronal ischemia-reperfusion.","authors":"Garrett M Fogo, Sarita Raghunayakula, Katlynn J Emaus, Francisco J Torres Torres, Gary Shangguan, Joseph M Wider, Maik Hüttemann, Thomas H Sanderson","doi":"10.1080/15548627.2025.2472586","DOIUrl":"10.1080/15548627.2025.2472586","url":null,"abstract":"<p><p>Mitochondrial damage and dysfunction are hallmarks of neuronal injury during cerebral ischemia-reperfusion (I/R). Critical mitochondrial functions including energy production and cell signaling are perturbed during I/R, often exacerbating damage and contributing to secondary injury. The integrity of the mitochondrial proteome is essential for efficient function. Mitochondrial proteostasis is mediated by the cooperative forces of mitophagy and intramitochondrial proteolysis. The aim of this study was to elucidate the patterns of mitochondrial protein dynamics and their key regulators during an <i>in vitro</i> model of neuronal I/R injury. Utilizing the MitoTimer reporter, we quantified mitochondrial protein oxidation and turnover during I/R injury, highlighting a key point at 2 h reoxygenation for aged/oxidized protein turnover. This turnover was found to be mediated by both LONP1-dependent proteolysis and PRKN/parkin-dependent mitophagy. Additionally, the proteostatic response of neuronal mitochondria is influenced by both mitochondrial fusion and fission machinery. Our findings highlight the involvement of both mitophagy and intramitochondrial proteolysis in the response to I/R injury.<b>Abbreviations</b>: cKO: conditional knockout; CLPP: caseinolytic mitochondrial matrix peptidase proteolytic subunit; DIV: days <i>in vitro</i>; DNM1L/DRP1: dynamin 1 like; ETC: electron transport chain; hR: hours after reoxygenation; I/R: ischemia-reperfusion; LONP1: lon peptidase 1, mitochondrial; mtUPR: mitochondrial unfolded protein response; OGD: oxygen glucose deprivation; OGD/R: oxygen glucose deprivation and reoxygenation; OPA1: OPA1 mitochondrial dynamin like GTPase; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROI: region of interest; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1492-1506"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Visualization of autophagic structures near solid polyQ aggregates reveals how they undermine autophagy.","authors":"Hana Popelka, Daniel J Klionsky","doi":"10.1080/15548627.2025.2503578","DOIUrl":"10.1080/15548627.2025.2503578","url":null,"abstract":"<p><p>Aggregates of polyglutamine (polyQ) repeat extensions are known markers of several, predominantly inherited, neurodegenerative diseases. Removal of polyQ is essential for cellular proteostasis and macroautophagy/autophagy has been proposed to be an important tool in the clearance of polyQ aggregates. The mechanism of recognition and encapsulation of these aggregates within autophagosomes is largely unknown. A study described in this article employed <i>in situ</i> correlative cryo-electron tomography to visualize polyQ aggregates interacting with autophagic compartments. The tomograms revealed that only amorphous polyQ, but not fibrils, are engulfed by double-membrane structures and that SQSTM1/p62 is the receptor involved in recognition of polyQ during autophagy. Solidified amorphous polyQ and subsequent fibrils arrest the normal formation of autophagosomes and impair autophagy. Findings of the study described here have implications for therapies that rely on autophagy in targeting polyQ neurodegeneration.<b>Abbreviation:</b> cryo-CLEM, cryo-correlative light and electron microscopy; cryo-ET, cryo-electron tomography; ER, endoplasmic reticulum; HD, Huntington disease; HTT, huntingtin; polyQ, polyglutamine repeats.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1393-1395"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMBOX1 reverses autophagy mediated 5-fluorouracil resistance through promoting HACE1-induced ubiquitination and degradation of ATG5 in colorectal cancer.","authors":"Yan Gao, Shenao Fu, Yinghui Peng, Yulai Zhou, Jiang Zhu, Xiangyang Zhang, Changjing Cai, Ying Han, Hong Shen, Shan Zeng","doi":"10.1080/15548627.2025.2477443","DOIUrl":"10.1080/15548627.2025.2477443","url":null,"abstract":"<p><p>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 <i>HMBOX1</i> 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 <i>in vitro</i> and <i>in vivo</i>. 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.<b>Abbreviation</b>: 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.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1556-1577"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leucine accelerates atherosclerosis through dose-dependent MTOR activation in macrophages.","authors":"Xiangyu Zhang, Ali Ajam, Ziyang Liu, Doureradjou Peroumal, Saifur R Khan, Babak Razani","doi":"10.1080/15548627.2025.2474603","DOIUrl":"10.1080/15548627.2025.2474603","url":null,"abstract":"<p><p>The role of diet in driving cardiovascular disease (CVD) is well-recognized, particularly in the case of lipids. Dietary protein on the other hand has been heralded as an overall metabolically beneficial nutrient with popularity in the fitness community and in weight-loss regimens. Pursuant to epidemiological studies raising a CVD risk signal for excessive protein intake, we initially conducted murine studies establishing an atherogenic role for dietary protein, the critical involvement of macrophage MTORC1 signaling, and downstream inhibition of protective macroautophagy/autophagy pathways. In recent work, we confirm these findings in monocytes from humans consuming protein and dissect the MTORC1-autophagy cascade in human macrophages. We also identify leucine as the single most important amino acid, observing dose-dependent activation of MTOR whereby only leucine concentrations above a threshold trigger pathogenic signaling and monocyte/macrophage dysfunction. Using mouse models fed diets with modulated protein and leucine content, we confirm this threshold effect in driving atherosclerosis. Our findings establish a pathogenic role for dietary leucine in CVD and raise the promise of therapeutic strategies aimed at selective inhibition of macrophage leucine-MTOR signaling.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1618-1620"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mitophagy receptor BNIP3L/Nix coordinates nuclear calcium signaling to modulate the muscle phenotype.","authors":"Jared T Field, Donald Chapman, Yan Hai, Saeid Ghavami, Adrian R West, Berkay Ozerklig, Ayesha Saleem, Julia Kline, Asher A Mendelson, Jason Kindrachuk, Barbara Triggs-Raine, Joseph W Gordon","doi":"10.1080/15548627.2025.2476872","DOIUrl":"10.1080/15548627.2025.2476872","url":null,"abstract":"<p><p>Mitochondrial quality control is critical in muscle to ensure contractile and metabolic function. BNIP3L/Nix is a BCL2 member, a mitophagy receptor, and has been implicated in muscle atrophy. Human genome-wide association studies (GWAS) suggest altered BNIP3L expression could predispose to mitochondrial disease. To investigate BNIP3L function, we generated a muscle-specific knockout model. <i>bnip3l</i> knockout mice displayed a ragged-red fiber phenotype, along with accumulation of mitochondria and endo/sarcoplasmic reticulum with altered morphology. Intriguingly, <i>bnip3l</i> knockout mice were more insulin sensitive with a corresponding increase in glycogen-rich muscle fibers. Kinome and gene expression analyses revealed that <i>bnip3l</i> knockout impairs NFAT and MSTN (myostatin) signaling, with alterations in muscle fiber-type and evidence of regeneration. Mechanistic experiments demonstrated that BNIP3L modulates mitophagy, along with reticulophagy leading to altered nuclear calcium signaling. Collectively, these observations identify novel roles for BNIP3L coordinating selective autophagy, oxidative gene expression, and signaling pathways that maintain the muscle phenotype.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1544-1555"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATG2A-WDR45/WIPI4-ATG9A complex-mediated lipid transfer and equilibration during autophagosome formation.","authors":"Yang Wang, Goran Stjepanovic","doi":"10.1080/15548627.2025.2473388","DOIUrl":"10.1080/15548627.2025.2473388","url":null,"abstract":"<p><p>Macroautophagy/autophagy is a highly conserved cellular process, spanning from yeast to humans, and plays a vital role in maintaining cellular homeostasis. Dysregulation of autophagy has been linked to a wide range of diseases. A hallmark of autophagy is the formation of double-membrane vesicles called autophagosomes. Autophagosome biogenesis requires a large number of phospholipids, with the endoplasmic reticulum (ER) being the main lipid source. The ATG2A-WDR45/WIPI4-ATG9A complex serves as the core machinery responsible for lipid transfer and equilibration during this process. In our recent study, we resolved the cryo-electron microscopy (cryo-EM) structures of the ATG2A-WDR45/WIPI4 and ATG2A-WDR45/WIPI4-ATG9A complexes, providing critical insights into their architecture and function. Additionally, molecular dynamics simulations were employed to investigate the mechanism by which ATG2A mediates lipid extraction from donor membranes. Our findings offer structural and mechanistic insights into the spatially coupled processes of lipid transfer and re-equilibration, which are essential for phagophore membrane expansion.<b>Abbreviation:</b> ATG: autophagy related; ATG2A: autophagy related 2A; ATG2A[NR]: ATG2A N-terminal region; ATG9A: autophagy related 9A; cryo-EM: cryo-electron microscopy; cryo-ET: cryo-electron tomography; ER: endoplasmic reticulum; PtdIns3P: phosphatidylinositol-3-phosphate; <i>Sp</i>Atg2[NR]: <i>Schizosaccharomyces pombe</i> Atg2 N-terminal region; SUVs: small unilamellar vesicles; TGN: trans-Golgi network; TMEM41B: transmembrane protein 41B; VMP1: vacuole membrane protein 1; WDR45/WIPI4: WD repeat domain 45.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1611-1613"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A classical anti-autophagic viral protein reshapes mitochondria for immune evasion.","authors":"Qing Zhu, Chengyu Liang","doi":"10.1080/15548627.2025.2522130","DOIUrl":"10.1080/15548627.2025.2522130","url":null,"abstract":"<p><p>Viral subversion of macroautophagy/autophagy is a well-established immune evasion strategy, with BCL2 homologs from γ-herpesviruses serving as prototypical inhibitors through BECN1 (beclin 1) sequestration. Yet the full spectrum of their functions remains incompletely understood. In our recent study, we uncovered a non-canonical role for the Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded BCL2 homolog (vBCL2) during late lytic replication. Unexpectedly, vBCL2 hijacks the host NDP kinase NME2/NM23-H2 to activate the mitochondrial fission GTPase DNM1L/DRP1, promoting mitochondrial fragmentation. This organelle remodeling dismantles MAVS-mediated antiviral signaling and facilitates virion assembly. A vBCL2 mutant unable to bind NME2 fails to induce fission or complete the viral lifecycle. These findings provide a long-sought answer to why vBCL2 is indispensable during lytic infection, and uncover a new immune evasion strategy centered on mitochondrial control. Our work expands the current view of virus-organelle interactions beyond canonical autophagy control and offers new targets for therapeutic intervention.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144509952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumorous cholesterol biosynthesis curtails anti-tumor immunity by preventing MTOR-TFEB-mediated lysosomal degradation of CD274/PD-L1.","authors":"Huina Wang, Xiuli Yi, Di Qu, Xiangxu Wang, Hao Wang, Hengxiang Zhang, Yuqi Yang, Tianwen Gao, Weinan Guo, Chunying Li","doi":"10.1080/15548627.2025.2519066","DOIUrl":"10.1080/15548627.2025.2519066","url":null,"abstract":"<p><p>Enhanced cholesterol biosynthesis is a hallmark metabolic characteristic of cancer, exerting an oncogenic role by supplying intermediate metabolites that regulate intracellular signaling pathways. The pharmacological blockade of cholesterol biosynthesis has been well documented as a promising therapeutic approach in cancer. Particularly, cholesterol biosynthesis is linked to macroautophagy/autophagy and lysosome metabolism, with the engagement of the critical autophagy regulators like MTOR to be fully activated by lysosomal cholesterol trafficking and accumulation. Previous studies have primarily focused on the role of cholesterol biosynthesis in tumor cell-intrinsic biological processes, whereas its involvement in tumor immune evasion and the underlying mechanisms related to autophagy or lysosome metabolism remain elusive. Herein, through bioinformatics analysis we discovered a negative correlation between cholesterol biosynthesis and the score of tumor-infiltrating lymphocytes in cancers. Inhibition of tumor cell cholesterol biosynthesis leads to increased infiltration and activation of CD8⁺ T cells in the tumor microenvironment, which is largely responsible for the impairment of tumor growth. Mechanistically, cholesterol biosynthesis inhibition impairs the activation of MTOR at lysosomes, thereby promoting the nuclear translocation of TFEB and downstream lysosome biosynthesis, facilitating the degradation of CD274/PD-L1 within lysosomes in tumor cells. Ultimately, the HMGCR-MTOR-LAMP1 axis that connects cholesterol, lysosome and tumor immunology, predicts poor response to immunotherapy and worse prognosis of patients with melanoma. These findings unveil an immunomodulatory role of tumorous cholesterol biosynthesis via the regulation of CD274 lysosomal degradation. Targeting cholesterol biosynthesis holds promise as a potential therapeutic strategy in cancer, particularly when combined with immune checkpoint blockade.<b>Abbreviations:</b> ATG5, autophagy related 5; CD274/PD-L1, CD274 molecule; CQ, chloroquine; CTLA4, cytotoxic T-lymphocyte associated protein 4; CHX, cycloheximide; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; GSVA, gene set variation analysis; GZMB, granzyme B; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; IFNG/IFN-γ, Interferon gamma; IHC, Immunohistochemistry; LAMP1, lysosomal associated membrane protein 1; MITF, melanocyte inducing transcription factor; MTOR, mechanistic target of rapamycin kinase; NK, natural killer; NSCLC, non-small cell lung cancer; PBMC, peripheral blood mononuclear cell; PDCD1/PD-1, programmed cell death 1; qRT-PCR, quantitative real-time polymerase chain reaction; SKCM, skin cutaneous melanoma; TCGA, The Cancer Genome Atlas; TFE3, transcription factor binding to IGHM enhancer 3; TFEB, transcription factor EB; TIL, tumor infiltrated lymphocyte; TME, tumor microenvironment; T_reg, regulatory T.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":0.0,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144287523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}