Autophagy最新文献

{"title":"A novel mitochondrial regulon for ferroptosis during fungal pathogenesis.","authors":"Qing Shen, Madiha Natchi Samu Shihabdeen, Fan Yang, Naweed I Naqvi","doi":"10.1080/15548627.2025.2546944","DOIUrl":"10.1080/15548627.2025.2546944","url":null,"abstract":"<p><p>Ferroptosis remains an underexamined iron- and lipid peroxides-driven cell death modality despite its importance to several human and plant diseases and to immunity thereof. Here, we utilized chemical cell biology, molecular genetics and biochemical analyses to gain insights into how the fungal pathogen <i>Magnaporthe oryzae</i> undergoes ferroptosis strictly in the spore cells to successfully transit to infectious development. We reveal a complex functional interdependency and crosstalk between intrinsic ferroptosis and autophagy-mediated mitochondrial degradation. Mechanistically, the requirement of mitophagy for ferroptotic cell death was attributed to its ability to maintain a pool of metabolically active mitochondria. Pharmacological disruption of the electron transport chain or membrane potential led to complete inhibition of ferroptosis, thus simulating the loss of mitophagy phenotypes. Conversely, increased mitochondrial membrane potential in a mitophagy-defective mutant alleviated the ferroptosis defects therein. Graded inhibition of mitochondrial coenzyme Q biosynthesis with or without ferroptosis inhibitor liproxstatin-1 distinguished its antioxidant function in such regulated cell death. Membrane potential-dependent regulation of ATP synthesis and iron homeostasis, as well as dynamics of tricarboxylic acid cycle enzyme AcoA (aconitase A) in the presence or absence of mitophagy, mitochondrial poisoning or iron chelation further linked mitochondrial metabolism to ferroptosis. Last, we present an important bioenergetics- and redox-based mitochondrial regulon essential for intrinsic ferroptosis and its precise role in fungal pathogenesis leading up to the establishment of the devastating rice blast disease.<b>Abbreviation</b>: 4-CBA: 4 chlorobenzoic acid; AcoA: aconitase A; Atg24: autophagy related 24; CoQ: coenzyme Q; CPX: ciclopirox olamine; ETC: electron transport chain; GSH: glutathione; Gpx4: glutathione peroxidase 4; HPI: hours post inoculation; MMP: mitochondrial membrane potential; MitoQ: Mitoquinone; ROS: reactive oxygen species; TCA: tricarboxylic acid.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-13"},"PeriodicalIF":14.3,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144823410","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":"Autophagic regulation of ferroportin 1 induces developmental ferroptosis in rice blast.","authors":"Ruhui Long, Meiling Liang, Qing Shen, Qiao Liu, Xing Wang, Naweed I Naqvi, Zhibin Liang, Yi Zhen Deng","doi":"10.1080/15548627.2025.2545471","DOIUrl":"10.1080/15548627.2025.2545471","url":null,"abstract":"<p><p>The rice blast fungus, <i>Magnaporthe oryzae</i>, imposes a great threat to global food security. Autophagic cell death of conidium is essential for appressorium-mediated host invasion during pathogenesis. Our recent study revealed that ferroptosis, potentially regulated by macroautophagy/autophagy, is responsible for <i>M. oryzae</i> conidial death during appressorium formation and maturation. Here, we characterized the role of the iron exporter MoFpn1 (ferroportin 1) and showed that its loss led to increased intracellular iron levels, accelerated conidial death, and reduced sensitivity to liproxstatin-1, suggesting that MoFpn1 negatively regulates ferroptosis as an iron exporter in <i>M. oryzae</i>. In conidia, MoFpn1-mCherry fusion protein localized on punctate/vesicular organelles, largely overlapping with CMAC-stained vacuoles, and is subject to regulation by iron availability and autophagy. MoFpn1 was associated with Atg8, based on yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays. MoFpn1-mCherry partially colocalized with GFP-Atg8-tagged autophagosomes or autophagic vacuoles in developing conidia. Upon appressorium formation, MoFpn1-mCherry localized to the plasma membrane of appressoria. In mature appressorium, plasma membrane-localized MoFpn1-mCherry transferred to the vacuolar lumen. MoFpn1 also directly interacted with components of the vesicular sorting complex, including the vacuolar SNARE Vam7 that mediates autophagosome-vacuole fusion. Individual deletion of <i>ATG8</i> or <i>VAM7</i> resulted in mislocalization of MoFpn1-mCherry to the vacuolar membrane or multivesicular bodies (MVBs) instead of the vacuolar lumen, under autophagy inducing conditions, or remained on the plasma membrane of the mature appressorium. Overall, our study demonstrates that regulation of the intracellular level of iron by Atg8- and Vam7-mediated autophagy-dependent degradation of MoFpn1 is crucial for conidial death and pathogenicity.<b>Abbreviations:</b> BiFC: bimolecular fluorescence complementation; CMAC: 7-amino-4-chloromethylcoumarin; Fpn1: ferroportin 1; Lip-1: liproxstatin-1; MDA: malondialdehyde; MVBs: multivesicular bodies; SNARE: soluble NSF attachment protein receptor; Y2H: yeast two-hybrid.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-16"},"PeriodicalIF":14.3,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144801217","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":"Pestivirus bovine viral diarrhea virus infection triggers lipophagy through the AMPK-PNPLA2/ATGL signaling pathway to promote viral replication.","authors":"Yingying Ma, Wenlu Fan, Yixin Wang, Jing Wang, Yuan Li, Xinyue Xia, Haiyue Zhu, Yue Lu, Guizhi Hou, Yujia Wang, Xinyuan Qiao, Houhui Song, Yigang Xu","doi":"10.1080/15548627.2025.2546934","DOIUrl":"10.1080/15548627.2025.2546934","url":null,"abstract":"<p><p>Macroautophagy/autophagy facilitates the catabolic process by degrading lipids within lysosomes, thereby maintaining cellular energy homeostasis. However, the precise mechanism by which bovine viral diarrhea virus (BVDV) induces autophagy to reprogram lipid metabolism remains unclear. In this study, we determined that BVDV infection depletes ATP and simultaneously induces the reprogramming of intracellular lipid metabolism. We also observed that BVDV infection promotes autophagy-dependent processing of lipid droplets and triglycerides, leading to the release of free fatty acids. The ATP content in BVDV-infected cells was reduced, resulting in an increased AMP:ATP ratio and subsequent phosphorylation of AMP-activated protein kinase (AMPK). Mechanistically, BVDV infection activates AMPK, subsequently enhancing lipophagy and facilitating viral replication. Our study further elucidates that PNPLA2/ATGL (patatin like domain 2, triacylglycerol lipase) may function as a downstream effector in the AMPK pathway, promoting lipophagy during BVDV infection. The BVDV nonstructural protein NS5A was found to induce autophagy via an AMPK-PNPLA2 pathway. Immunoprecipitation assays demonstrated that NS5A interacts with BECN1 and PNPLA2. These findings suggest that BVDV infection modulates lipophagy by regulating the AMPK-PNPLA2 pathway, thereby mobilizing energy for its replication. Overall, our data suggest that targeting the AMPK-PNPLA2 pathway could serve as a novel host-directed antiviral strategy, offering significant insights for the development of innovative BVDV vaccines and therapeutic drugs.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":14.3,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144823411","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":"Inhibition of UBE2N promotes the clearance of mutant HTT (huntingtin) in HD knock-in mice.","authors":"Kaili Ou, Xiang Wang, Mingwei Guo, Dandan Li, Chen Zhang, Laiqiang Chen, Junqi Hou, Qingqing Jia, Longhong Zhu, Su Yang, Shihua Li, Xiao-Jiang Li, Peng Yin","doi":"10.1080/15548627.2025.2549109","DOIUrl":"https://doi.org/10.1080/15548627.2025.2549109","url":null,"abstract":"<p><p>Accumulation of misfolded proteins leads to many neurodegenerative diseases that can be treated by lowering or removing mutant proteins. Huntington disease (HD) is characterized by the accumulation of ubiquitinated mutant HTT (huntingtin) in the central nervous system. Ubiquitination of the misfolded proteins, a common feature of the neurodegenerative diseases, is mediated by the different lysine residues on ubiquitin. We previously discovered that the age-dependent increase of UBE2N (ubiquitin conjugating enzyme E2 N) exacerbated the accumulation of misfolded HTT and amyloid proteins, accompanied by the elevation of K63 ubiquitination. Pharmacological inhibition of UBE2N could ameliorate the amyloid deposition. However, the effect of UBE2N suppression on HTT aggregate clearance has remained unknown. In the current work, we demonstrate that selectively suppressing UBE2N, with antisense oligonucleotides or small-molecular inhibitors, increased removal of HTT aggregates by proteasome degradation in the striatum of HD knock-in mice. We also identified two novel ubiquitin specific peptidases, USP29 and USP49, that participated in the clearance of HTT aggregates, via accelerating K48-mediated ubiquitin-proteasome function. Our findings provide a potential pharmacological approach to treat neurodegeneration caused by mutant HTT.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862694","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":"Contrasting roles of autophagy in cellular prion infection.","authors":"Basant Abdulrahman, Andreas Heiseke, Yasmine Aguib, Li Lu, Dalia Abdelaziz, Mariam Ansari, Simrika Thapa, Yuzuru Taguchi, Sabine Gilch, Hermann M Schätzl","doi":"10.1080/15548627.2025.2545604","DOIUrl":"10.1080/15548627.2025.2545604","url":null,"abstract":"<p><p>Autophagy is a cellular degradation program that can exert both beneficial and adverse effects in various neurodegenerative diseases. We tested the role of macroautophagy/autophagy in prion infection and how this machinery affects the life cycle of prions. In mouse embryonic fibroblasts, we found a pronounced dependence of prion replication on autophagy competence, suggesting that autophagy provides functions needed for prion propagation. However, in neuronal cells, autophagy had mostly the opposite role. Cells ablated for autophagy competence by gene editing harbored elevated amounts of misfolded prion protein, indicating that neuronal cells use autophagy for prion degradation. These data show that autophagy can have two functions in the replication of prions, and depending on the cellular context, this can be protective against or supportive of prion infection. These findings demonstrate that prions use cellular machineries to benefit propagation in certain cell types, whereas other cell types employ the same machinery as a defense mechanism.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-19"},"PeriodicalIF":14.3,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805424","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":"GSTK1 and RETREG1/FAM134B-mediated reticulophagy attenuates tubular injury in diabetic nephropathy through endoplasmic reticulum stress and apoptosis.","authors":"Shumin Zhang, Wei Chen, Wenpeng Wang, Yifei Liu, Chanyue Zhao, Kexin Yang, Wenni Dai, Yanglei Ou, Xiangxiang Yin, Yangjun Long, Yu Liu, Lei Zhang, Lin Sun, Fuyou Liu, Li Xiao","doi":"10.1080/15548627.2025.2541385","DOIUrl":"https://doi.org/10.1080/15548627.2025.2541385","url":null,"abstract":"<p><p>Reticulophagy is a key process to recovery from endoplasmic reticulum (ER) stress and for maintaining ER homeostasis by selectively removing damaged ER and its components. However, its precise mechanisms in diabetic nephropathy (DN) remain unclear. Here, we found that the expression of RETREG1/FAM134B (reticulophagy regulator 1) was decreased in the tubular cells in DN patients and animal models, which was positively correlated with estimated glomerular filtration rate (eGFR) and negatively associated with tubulointerstitial damage. Proximal tubule-specific knockout of <i>Retreg1</i> exacerbated reticulophagy abnormalities in diabetic mice induced by high-fat diet (HFD) combined with streptozotocin (STZ), which was accompanied by increased ER stress, apoptosis of tubular cells and tubulointerstitial fibrosis. <i>In vitro</i>, overexpression of RETREG1 notably restored reticulophagy, and alleviated ER stress and apoptosis in HK-2 cells, a human proximal tubular cell line, treated with high glucose. Mechanistically, immunoprecipitation coupled with mass spectrometry (IP-MS) suggested that RETREG1 could interact with GSTK1 (glutathione s-transferase kappa 1). Silencing of GSTK1 further aggravated the reduction of reticulophagy and tubular injury both <i>in vivo</i> and <i>in vitro</i>. These effects in <i>in vitro</i> were partially blocked by overexpressing RETREG1. Collectively, these findings suggest that GSTK1 and RETREG1 exert a protective role in tubular injury through restoring reticulophagy and mitigating ER stress of tubular cells in DN.<b>Abbreviation</b>: ACTB: actin beta; cCASP3: cleaved caspase 3; CANX: calnexin; CASP: caspase; Co-IP: co-immunoprecipitation; DDIT3: DNA damage-inducible transcript 3; DN: diabetic nephropathy; ER: endoplasmic reticulum; FN1: fibronectin 1; GSTK1: glutathione S-transferase kappa 1; HFD: high-fat diet; HG: high glucose; HK-2: human tubular cell; HSPA5: heat shock protein family A (Hsp70) member 5; IHC: immunohistochemistry; IF: immunofluorescence; IP MS: immunoprecipitation coupled with mass spectrometry; LIR: LC3-interacting region; LTL: Lotus tetragonolobus lectin; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PACS2: phosphofurin acidic cluster sorting protein 2; PTCs: proximal tubular cells; PT: proximal tubule; RETREG1/FAM134B: reticulophagy regulator 1; RHD: reticulon homology domain; RT-qPCR: real time-quantitative PCR; SQSTM1/p62: sequestosome 1; STZ: streptozotocin; TECs: tubular epithelial cells; TEM: transmission electron microscopy; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; UACR: urine albumin creatine ratio; UPR: unfolded protein response.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-16"},"PeriodicalIF":14.3,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144801218","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":"Dysfunctional autophagy triggers STING1 activation to exacerbate cartilage degeneration in obesity-associated osteoarthritis.","authors":"Xiaomin Kang, Wenjuan Liu, Xiao Ma, Dongxu Feng, Hongzhi Sun, Shufang Wu","doi":"10.1080/15548627.2025.2541388","DOIUrl":"10.1080/15548627.2025.2541388","url":null,"abstract":"<p><p>Obesity, a major risk factor for osteoarthritis (OA), is related to increased circulating levels of free fatty acids (FFAs). However, the molecular mechanism underlying this metabolic OA phenotype remains unknown. We found that mice fed a high-fat diet (HFD) became obese and developed OA in their knee joints. Macroautophagy/autophagy activity was significantly reduced in articular cartilage of mice fed an HFD or in chondrocytes exposed to FFAs. Using conditional knockout (cKO) mice with cartilage-specific deletion of <i>Atg7</i> to inhibit autophagy <i>in vivo</i> and sh<i>Atg7</i>-lentiviral-transduced chondrocytes in <i>vitro</i>, we showed that autophagy deficiency aggravated HFD-induced OA progression and chondrocyte extracellular matrix (ECM) degradation. Mechanistically, STING1 was degraded in an autophagy-dependent manner. Autophagy deficiency increased STING1 levels, in turn activating the STING1-TBK1-IRF3 and MAP2K3/MKK3-MAPK/p38 signaling pathways, thereby triggering cartilage ECM degradation. These findings suggested that the HFD-autophagy-STING1 axis played a pivotal role in OA development, providing a potential therapeutic strategy for obesity-associated OA.<b>Abbreviation</b>: 3-MA: 3-methyladenine; ACAN: aggrecan; AOD: average optical density; ATG7: autophagy related 7; BafA1: bafilomycin A1; CGAS: cyclic GMP-AMP synthase; cKO: conditional knockout; COL2A1: collagen, type II, alpha 1; DMM: destabilizing the medial meniscus; DMXAA: 5.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-17"},"PeriodicalIF":14.3,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736000","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 cell autonomous and non-autonomous functions of Rab27 in longevity and neuroprotection in <i>Drosophila</i>.","authors":"Chia-Heng Hsu, Yi-Jhan Li, Ting-Ni Guo, Fei-Yang Tzou, Cheng-Li Hong, Chin-Hsien Lin, Shu-Yi Huang, Chih-Chiang Chan","doi":"10.1080/15548627.2025.2541384","DOIUrl":"https://doi.org/10.1080/15548627.2025.2541384","url":null,"abstract":"<p><p>Autophagic decline accompanies age and causes a deterioration in proteostasis, rendering neuronal demise. Rab27 functions as a vesicle regulator for macroautophagic/autophagic degradation and exocytosis. Loss of <i>Drosophila Rab27</i> in αβp brain neurons enhances longevity, underscoring its neuronal role and systemic effect. To understand the underlying mechanisms, we characterized the cell autonomous and non-autonomous functions of <i>Rab27</i>. <i>Rab27</i> expression increased in midlife, providing a temporal manipulation window. Depleting <i>Rab27</i> at that timepoint activated autophagy and sustained neuronal maintenance. At the organismic level, Egfr (Epidermal growth factor receptor) ligand was reduced and Akt kinase underphosphorylated in the <i>Rab27</i> KO fly body, indicating a widespread signaling cascade. Finally, <i>Rab27</i> KO ameliorates the neurotoxicity in a fly α-synucleinopathy model. Altogether, our results highlight a neuronal autophagy regulator exerting systemic effects that are crucial for neuronal maintenance and improving longevity.<b>Abbreviation</b>: Atg autophagy-related genes;EGF: epidermal growth factor; Egfr: Epidermal growth factor receptor;EGFR: epidermal growth factor receptor; foxo: forkhead box, sub-groupO; mTor: mechanistic target of rapamycin; MTOR: mechanistic target ofrapamycin; spi: spitz.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-17"},"PeriodicalIF":14.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144791016","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":"Apoptotic bodies derived from human umbilical cord mesenchymal stem cells improve recovery from myocardial infarction in swine.","authors":"Wei Luo, Hao Li, Pengfei Zhang, Hao Cao, Yun Dong, Yanshan Gong, Dongling Zhu, YuanFeng Xin, Zhongmin Liu, Ling Gao","doi":"10.1080/15548627.2025.2536449","DOIUrl":"10.1080/15548627.2025.2536449","url":null,"abstract":"<p><p>Apoptotic bodies (ABs) are a type of extracellular vesicles (EVs) that could contribute to the paracrine effect of stem cells. However, their potential in treating cardiovascular diseases is largely unexplored. This study investigated the therapeutic effects of ABs derived from human umbilical cord mesenchymal stem cells (MSCs) on cardiac recovery in a porcine model of myocardial infarction (MI). In vitro, ABs reduced apoptosis and cytotoxicity in cardiomyocytes under oxygen and glucose deprivation (OGD) conditions and enhanced the capacity of migration and tube formation in endothelial cells. In vivo, akin to MSCs, administration of ABs improved contractile function, reduced infarct size, and mitigated adverse remodeling in pig hearts with MI, concomitantly with increased cardiomyocyte survival and angiogenesis. These cardioprotective effects were mediated through the regulation of autophagy by activating the adenosine monophosphate - activated protein kinase (AMPK) and transcription factor EB (TFEB) signaling pathways. microRNAs contained in ABs were sequenced, revealing that let-7f-5p was the most abundant. let-7f-5p promoted AMPK phosphorylation by targeting protein phosphatase 2 regulatory subunit B alpha (PPP2R2A) and decreased TFEB phosphorylation by targeting MAP4K3 to regulate autophagy, thereby contributing to the effects of ABs. Overall, these findings indicate that MSC-derived ABs have the potential to be a promising and effective acellular therapeutic option for treating MI.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":14.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669070","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":"Autophagy suppression via SRC induction represents a therapeutic vulnerability for <i>BAP1</i>-mutant cancers.","authors":"Silvia Vega-Rubin-de-Celis, Amanda Kristani, Matthias Kudla, Svenja Mergener, Andrés Corrochano-Ruiz, Safa Larafa, Jetsy Montero-Vergara, Laura-Marie Ahle, Rainer Will, Mael Lever, Viktor Grünwald, Boris Hadaschik, Verena Jendrossek, Nikolaos E Bechrakis, Samuel Peña-Llopis","doi":"10.1080/15548627.2025.2535265","DOIUrl":"https://doi.org/10.1080/15548627.2025.2535265","url":null,"abstract":"<p><p>BAP1 is a tumor suppressor and epigenetic modifier that is frequently mutated in cancer, leading to increased aggressiveness and metastasis, as well as poor patient survival. Unfortunately, there are currently no specific therapies for metastatic tumors harboring <i>BAP1</i> mutations. In this study, we have identified a new targetable BAP1-associated autophagic vulnerability. We demonstrate that BAP1 transcriptionally regulates the proto-oncogene SRC, a non-receptor tyrosine kinase. SRC then binds to, phosphorylates, and inactivates BECN1 (Beclin 1), an essential autophagy protein. This inhibits autophagy in cells derived from various cancer types with <i>BAP1</i> mutations. Treatment of these cells with SRC inhibitors (such as dasatinib, bosutinib and saracatinib) and autophagy-inducing drugs (such as Tat-BECN1, SW076956 and SW063058) demonstrated a synergistic interaction between these compounds both <i>in vitro</i> and <i>in ovo</i> using a chick Chorioallantoic Membrane (CAM) assay. Furthermore, <i>ex vivo</i> studies employing patient-derived tumor organoids (PDTOs) of uveal melanoma (UM) and clear-cell renal cell carcinoma (ccRCC) as preclinical models have substantiated the synergism of these drugs, preferentially in the context of BAP1 loss. Our findings elucidate a novel BAP1-SRC-BECN1-autophagy regulatory axis that can be exploited therapeutically in precision oncology through the combination of SRC inhibitors and autophagy inducers, contingent upon patient stratification for BAP1 loss.<b>Significance</b>: Deadly cancers with <i>BAP1</i> mutations suppress autophagy by phosphorylating the autophagy regulator BECN1 via the proto-oncogene SRC. Treatment with SRC inhibitors and autophagy inducers exhibited synergism <i>in</i> <i>vitro</i>, <i>in ovo</i> and in patient-derived tumor organoids with BAP1 loss, paving the way for treating BAP1-deficient cancers with autophagy inducers and kinase inhibitors.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":14.3,"publicationDate":"2025-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777190","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}