Autophagy最新文献

{"title":"Defective autophagy in a fibroin secretion-deficient silkworm mutant.","authors":"Jianhua Xia, Haiqin Chen, Yuying Wang, Wenbo Hu, Kaiyu Guo, Qingqing Linghu, Pengchao Guo, Xin Wang, Qingyou Xia, Ioannis P Nezis, Ping Zhao, Zhaoming Dong, Yan Zhang","doi":"10.1080/15548627.2025.2510843","DOIUrl":"https://doi.org/10.1080/15548627.2025.2510843","url":null,"abstract":"<p><p>The silkworm <i>Bombyx mori</i> is an economically important insect for silk production. Its silk glands are responsible for the synthesis and secretion of silk proteins. The naked pupa (<i>Nd</i>), a fibroin heavy chain mutant strain of silkworm, was found to exhibit severe atrophy, degeneration of the posterior silk gland (PSG), and abnormal secretion of fibroin proteins, thereby producing little or no silk. Here, we found that the autophagic marker Atg8-PE was upregulated through the target of rapamycin complex 1 signaling pathway in <i>Nd</i>. However, as autophagy substrates, SQSTM1/p62 and ubiquitinated protein levels increased in <i>Nd</i>. Furthermore, treatment with BafA1 showed no effect on the protein levels of SQSTM1/p62, indicating impaired autophagic flux in <i>Nd</i>. Abnormal acidification of lysosomes was further detected, which resulted in a decreased proportion of matured CtsL1 (cathepsin L1). Thus, the substrate in autolysosomes cannot be degraded within a rapid time frame, resulting in the accumulation of protein aggregates, which cause atrophy and degeneration of the PSG. We also found that acidic nanoparticles rescued lysosomal acidification and relieved the degenerative changes of <i>Nd</i>-PSG. The findings of this study suggest that the <i>Nd</i> mutant silkworm can be used as an animal model for studying protein aggregation diseases.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144903","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":"Endoplasmic reticulum tubule junctions are sites of autophagy.","authors":"Susan Ferro-Novick","doi":"10.1080/15548627.2025.2508934","DOIUrl":"https://doi.org/10.1080/15548627.2025.2508934","url":null,"abstract":"<p><p>Selective endoplasmic reticulum (ER) macroautophagy/autophagy, also called reticulophagy, is a disposal pathway that degrades ER domains. A major role of reticulophagy is the removal of ER domains that contain misfolded proteins resistant to ER-associated degradation (ERAD). Our studies have shown that RTN3L, the SEC24C-SEC23 COPII coat subcomplex, and the CUL3^KLHL12 E3 ligase that ubiquitinates RTN3L targets ERAD-resistant misfolded protein condensates for degradation at <u><b>ER</b>-reticulo<b>ph</b>agy <b>s</b></u>ites (ERPHS), autophagic sites that form at tubule junctions. Unexpectedly, we found that the Parkinson disease protein PINK1 regulates ER tubulation. Loss of PINK1 disrupts the formation of peripheral tubule junctions, and, as a consequence, reticulophagy is blocked and misfolded proteins accumulate in the ER. Overexpression of the ER tubulating domain of DNM1L/DRP1, a multifunctional PINK1 kinase substrate that localizes to ER-mitochondria contact sites, increases junctions and restores reticulophagy. Our findings show that PINK1 shapes the ER to target misfolded proteins for RTN3L-SEC24C-mediated macroreticulophagy at defined ER sites, peripheral tubule junctions.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144842","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 pathway of autophagy in the epigenetic landscape of <i>Mycobacterium</i>-host interactions.","authors":"Abhishek Mishra, Varsha Rawat, Kangling Zhang, Chinnaswamy Jagannath","doi":"10.1080/15548627.2025.2511074","DOIUrl":"https://doi.org/10.1080/15548627.2025.2511074","url":null,"abstract":"<p><p>Macroautophagy (autophagy) is an evolutionarily conserved process that degrades excess cytoplasmic components, such as protein aggregates and damaged organelles, by encapsulating them within double-membrane autophagosomes. These autophagosomes undergo distinct stages - initiation, phagophore nucleation, expansion, and closure - before fusing with lysosomes (or occasionally endosomes) for degradation and recycling. This process is regulated by ATG (autophagy related) proteins, which govern autophagosome formation and lysosomal fusion. Epigenetic modifications and transcription factors can regulate <i>ATG</i> gene expression in the nucleus. Autophagy also plays a key role in eliminating intracellular <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) through the lytic and antimicrobial activities of autolysosomes, which are more potent antimicrobial compartments than conventional phagosomes. Emerging evidence suggests that <i>Mtb</i> can modify the host epigenome and transcriptional machinery, significantly affecting the host immune response. This review explores the epigenetic regulation of autophagy during mycobacterium-host interactions. The interplay between epigenetic regulation and autophagy highlights a crucial aspect of host-pathogen interactions during <i>Mtb</i> infection. Understanding how <i>Mtb</i> manipulates the host epigenome to regulate autophagy could lead to the development of novel therapeutic strategies that enhance autophagic pathways or counteract <i>Mtb's</i> immune evasion tactics.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144846","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":"TRIM16 mediates secretory autophagy in head and neck cancer-associated fibroblasts.","authors":"Thuc Ly, Bailey Pickard, Avisha Pandey, Marrion Yap, Julia Opara, Levi Arnold, Noraida Martinez-Rivera, Eduardo Rosa-Molinar, Jacob New, Lauryn Werner, Nathan Farrokhian, Sumedha Gunewardena, Maura O'Neil, Andres Bur, Shrikant Anant, Michael P Washburn, Carlo Barnaba, Wen-Xing Ding, Sufi Mary Thomas","doi":"10.1080/15548627.2025.2508064","DOIUrl":"10.1080/15548627.2025.2508064","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Improving treatment options for head and neck squamous cell carcinoma (HNSCC) requires a deeper understanding of the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs). We previously reported that HNSCC-derived FGF2/bFGF (fibroblast growth factor 2) triggers cytokine release from CAFs via secretory autophagy. Here, using transmission electron microscopy, live-cell imaging, and immunofluorescence, we show that CAF autophagosomes transport cargo, including IL6, to the plasma membrane for secretion. Autophagy in CAFs is constitutive and independent of STAT3, MAPK1/ERK2-MAPK3/ERK1 and phosphoinositide 3-kinase (PI3K) signaling. Despite the significant role of secretory autophagy in CAFs, its molecular machinery has remained elusive. Using both a literature based, and an unbiased approach, we studied the molecular machinery involved in autophagosome trafficking in CAFs. We identified TRIM16, a protein previously reported to traffic to autophagosomes, upregulated in CAFs compared to normal oral fibroblasts. Immunohistochemistry of patient HNSCC stroma revealed co-expression of TRIM16 and LC3B, linking TRIM16 to autophagosome function. An unbiased proteomics profiling of immunoprecipitated LC3B&lt;sup&gt;+&lt;/sup&gt; vesicles in primary HNSCC CAFs revealed enrichment in trafficking proteins, focal adhesion, and mitochondrial proteins. We demonstrate that SEC22B, SNAP23, VAMP3, and STX4 colocalize with LC3B, IL6, and TRIM16 in CAFs. TRIM16 knockdown reduced autophagosomes at the plasma membrane and decreased IL6 secretion from CAFs. These findings uncover key molecular components involved in autophagy-mediated IL6 secretion in CAFs and suggest potential therapeutic targets for HNSCC.&lt;b&gt;Abbreviations&lt;/b&gt;: ACTA2/αSMA: actin alpha 2, smooth muscle; CAF: cancer-associated fibroblasts; CM: conditioned media; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DMSO: dimethylsulfoxide; EGFP: enhanced green fluorescent protein; ELISA: enzyme-linked immunosorbent assay; ER: endoplasmic reticulum; FGF2/bFGF: fibroblast growth factor 2; FGFR: fibroblast growth factor receptor; GO: gene ontology; GORASP2/GRASP55: golgi reassembly stacking protein 2; HMGB1: high mobility group box 1; HNSCC: head and neck squamous cell carcinoma; HPV: human papillomavirus; IL6: interleukin 6; IP: immunoprecipitation; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPK3/ERK1: mitogen-activated protein kinase 3; NFs: normal oral fibroblasts; NSCLC: non-small cell lung cancer; PLA: proximity ligation assay; SQSTM1/p62: sequestosome 1; STAT3: signal transducer and activator of transcription 3; SNAP23: synaptosome associated protein 23; SNARE: soluble N-ethyl-maleimide-sensitive factor attachment protein receptor; STX4: syntaxin 4; TEM: transmission electron microscopy; TGFB1: transforming growth factor be","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-24"},"PeriodicalIF":0.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144096189","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 degradation of SQSTM1 enables fibroblast activation to accelerate wound healing.","authors":"Yujiao Xu, Xin Gu, Wenshu Li, Boyang Lin, Yiting Xu, Qingcheng Wei, Qingyuan Liu, Yamin Zhao, Rongzhuo Long, Hulin Jiang, Zhaoqiu Wu, Yunyao Liu, Lei Qiang","doi":"10.1080/15548627.2025.2508546","DOIUrl":"https://doi.org/10.1080/15548627.2025.2508546","url":null,"abstract":"<p><p>Wound healing is a meticulously coordinated and intricate progression that necessitates precise regulation of fibroblast behavior. Macroautophagy/autophagy is a degradation system for clearing damaged cellular components. SQSTM1/p62 (sequestosome 1), a well-established autophagy receptor, also functions as a signaling hub beyond autophagy. Here, we observed a significant upregulation of autophagy in fibroblasts after wounding. Using mice with fibroblast-specific deletion of <i>Atg7</i> (autophagy related 7), we found that fibroblast autophagy governed wound healing. Fibroblast autophagy deficiency delayed proper dermal repair that was mired in insufficient fibroblast proliferation, migration, and myofibroblast transition. <i>In vitro</i> experiments further revealed that autophagy deficiency disrupted TGFB1 (transforming growth factor beta 1)-induced fibroblast proliferation, migration, and myofibroblast differentiation. Mechanistically, autophagy deficiency led to SMAD2 (SMAD family member 2) and SMAD3 sequestration within SQSTM1 bodies and attenuated TGFB1-induced receptor-regulated SMAD (R-SMAD) phosphorylation in an SQSTM1-dependent manner. Furthermore, <i>sqstm1</i> deletion rescued the delayed skin wound healing caused by autophagy deficiency, and autophagy inducers promoted wound healing in an SQSTM1-dependent manner. Our findings highlight the critical role of fibroblast autophagy in wound healing and elucidate the underlying mechanisms by which autophagy regulates fibroblast behavior.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121630","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":"S-palmitoylation coordinates the trafficking of ATG9A to mediate autophagy initiation.","authors":"Fan Xia, Weining Li, Wenru Wang, Jiru Liu, Xiaolin Li, Jing Cai, Hao Shan, Zhe Cai, Jun Cui","doi":"10.1080/15548627.2025.2509376","DOIUrl":"https://doi.org/10.1080/15548627.2025.2509376","url":null,"abstract":"<p><p>Macroautophagy (hereafter autophagy), a major intracellular catabolic process, is evolutionarily conserved from yeasts to mammals, and is associated with a broad range of human diseases. Autophagy is morphologically characterized by the formation of double-membrane autophagosomes. ATG9A, a multi-spanning transmembrane protein and lipid scramblase, is a core component of the autophagy machinery that complements membrane sources and equilibrates lipids across membrane bilayers. Here, we report that palmitoyltransferase ZDHHC5 is indispensable for autophagosome nucleation and subsequent autophagosome formation. Upon autophagy induction, ZDHHC5 is internalized from the plasma membrane into intracellular compartments via clathrin-mediated endocytosis. This enzyme activates ATG9A S-palmitoylation at cysteine 155/156, which orchestrates the interaction of ATG9A with the heterotetrameric adaptor protein complex family member AP4E1/AP-4ε and subsequent trafficking from the trans-Golgi network to endosomal compartments. Functionally, impairment of ATG9A S-palmitoylation results in defects in autophagy initiation and autophagosome formation. These findings identify a regulatory mechanism that coordinates ATG9A-binding with AP4E1 and vesicular trafficking events through ATG9A S-palmitoylation by ZDHHC5, thereby ensuring the spatiotemporal fidelity of membrane trafficking and maintenance of autophagic homeostasis.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112994","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":"SENP2-mediated deSUMOylation of NCOA4 protects against ferritinophagy-dependent ferroptosis in myocardial ischemia-reperfusion injury.","authors":"Siyuan Xue, Jiaxin Zeng, Jingzhe Hao, Wanzhi Cai, Yuxuan Ding, Yuelin Chao, Zong Miao, Guanhua Xu, Lei Xu, Zeyu Jiang","doi":"10.1080/15548627.2025.2504792","DOIUrl":"10.1080/15548627.2025.2504792","url":null,"abstract":"<p><p>Myocardial ischemia-reperfusion (MI/R) injury is a leading cause of morbidity and mortality around the world, characterized by injury to cardiomyocytes that leads to various forms of cell death, including necrosis, apoptosis, autophagy, and ferroptosis. Preventing cell death is crucial for preserving cardiac function after ischemia-reperfusion injury. Ferroptosis, a novel type of cell death, has recently been identified as a key driver of cardiomyocyte death following MI/R. However, the complex regulatory mechanisms involved in ferroptosis remain unclear. Here, we found that SENP2 expression decreased following myocardial ischemia reperfusion injury. Deletion of <i>SENP2</i> increased cardiomyocyte ferroptosis and hindered cardiac function recovery after MI/R injury, whereas overexpression of SENP2 significantly reduced cardiomyocyte ferroptosis and mitigated MI/R injury. Mechanistically, SENP2 removed the SUMOylation of NCOA4 modified by SUMO1 at K81, K343, and K600 sites. The level of NCOA4 SUMOylation regulated ferritinophagy-dependent ferroptosis through affecting NCOA4 protein stability. SENP2-mediated NCOA4 deSUMOylation alleviated the interaction between NCOA4 and OTUB1, which directly deubiquitinated NCOA4 and maintained its protein stability. Furthermore, administration of SENP2 in the animal MI/R model reduced ferroptosis events, protected the injured myocardium and promoted cardiac function recovery. Collectively, our results demonstrate that SENP2 catalyzes deSUMOylation of NCOA4, alleviates ferritinophagy-mediated ferroptosis in an OTUB1-dependent manner, thereby facilitating cardiac function recovery following MI/R. These findings suggest a potential therapeutic strategy for MI/R treatment.<b>Abbreviations</b>: I/R: ischemia-reperfusion; MI/R: myocardial ischemia-reperfusion; NCOA4: nuclear receptor coactivator 4; OTUB1: OTU domain, ubiquitin aldehyde binding 1; SENP2: SUMO/sentrin specific peptidase 2.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-18"},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032100","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":"CircRNA <i>GRAMD4</i> induces <i>NBR1</i> expression to promote autophagy and immune escape in renal cell carcinoma.","authors":"Mi Zhou, Minyu Chen, Zhousan Zheng, Qihao Li, Lican Liao, Yunfei Wang, Yi Xu, Guannan Shu, Junhang Luo, Taowei Yang, Jiaxing Zhang","doi":"10.1080/15548627.2025.2503560","DOIUrl":"https://doi.org/10.1080/15548627.2025.2503560","url":null,"abstract":"<p><p>The tumor microenvironment (TME) in renal cell carcinoma (RCC) frequently exhibits significant immune cell infiltration. However, tumor cells often manage to evade immune surveillance. This study revealed the mechanism by which circular RNA <i>circGRAMD4</i> regulates <i>NBR1</i>. <i>CircGRAMD4</i> is markedly elevated in RCC, and its high levels are correlated with a poor prognosis. Notably, the absence of <i>circGRAMD4</i> has been demonstrated to result in a significant inhibition of renal cancer cell growth. This inhibition has been attributed to an enhanced anti-tumor immunity mediated by CD8⁺ T cells. Mechanistically, <i>circGRAMD4</i> interacts with the RBM4 protein, stabilizing the autophagic cargo receptor <i>NBR1</i> mRNA. This interaction promotes <i>NBR1</i> expression, which in turn leads to the degradation of MHC-I molecules through macroautophagy/autophagy pathways. Consequently, this process affects renal cancer cell antigen presentation, induces CD8⁺ T cell dysfunction, and contributes to tumor immune escape. Moreover, by inhibiting <i>circGRAMD4</i> and using immune checkpoint blockers (ICB), the immunosuppressive TME is altered to prevent tumor immune evasion, ultimately increasing the effectiveness of ICB treatment. The discovery highlights the significant impact of <i>circGRAMD4</i> on RCC immune escape and proposes that blocking <i>circGRAMD4</i> could serve as a promising immunotherapy strategy when combined with ICB to enhance patient outcomes.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-21"},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082724","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":"Epilepsy and autophagy modulators: a therapeutic split.","authors":"Hayder M Al-Kuraishy, Majid S Jabir, Ali I Al-Gareeb, Ali K Albuhadily, Daniel J Klionsky, Mayyadah F Rafeeq","doi":"10.1080/15548627.2025.2506292","DOIUrl":"https://doi.org/10.1080/15548627.2025.2506292","url":null,"abstract":"<p><p>Epilepsy is a neurological disease characterized by repeated unprovoked seizure. Epilepsy is controlled by anti-epileptic drugs (AEDs); however, one third of epileptic patients have symptoms that are not controlled by AEDs in a condition called refractory epilepsy. Dysregulation of macroautophagy/autophagy is involved in the pathogenesis of epilepsy. Autophagy prevents the development and progression of epilepsy through regulating the balance between inhibitory and excitatory neurotransmitters. Induction of autophagy and autophagy-related proteins could be a novel therapeutic strategy in the management of epilepsy. Despite the protective role of autophagy against epileptogenesis and epilepsy, its role in status epilepticus is perplexing and might reflect its nature as a double-edged sword. Autophagy inducers play a critical role in reducing seizure frequency and severity, and could be an adjuvant treatment in the management of epilepsy. However, autophagy inhibitors also have an anticonvulsant effect. Therefore, the aim of the present mini-review is to discuss the potential role of autophagy in the pathogenesis of epileptogenesis and epilepsy, and how autophagy modulators affect epileptogenesis and epilepsy.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082728","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":"SFTSV induces liver ferroptosis through m6A-related ferritinophagy.","authors":"Bingxin Liu, Xiaoyan Tian, Linrun Li, Na Jiang, Min Cheng, Jin Zhu, Zhiwei Wu","doi":"10.1080/15548627.2025.2503564","DOIUrl":"https://doi.org/10.1080/15548627.2025.2503564","url":null,"abstract":"<p><p>Severe fever with thrombocytopenia syndrome (SFTS) is a widely prevalent infectious disease caused by severe fever with thrombocytopenia syndrome virus (SFTSV). SFTSV infection carries a high mortality rate and has emerged to be a public health concern. SFTSV infection could induce many classical cell death pathways. Ferroptosis, a novel iron-dependent form of regulated cell death, is shown to participate in various biological processes and is considered as a new therapeutic target. In the current study, we reported that SFTSV infection perturbed the classical redox cycle by downregulating the expression of GPX4, SLC7A11 and GSH, and increasing the level of reactive oxygen species (ROS) and malondialdehyde (MDA). Interestingly, we observed that the elevation of <i>ATG5</i> mRNA m6A modification after SFTSV infection and mutation of the m6A-sites significantly rescued SFTSV infection-induced ferritinophagy. We further found that the NSs protein of SFTSV played a major role in driving the ferritinophagy. Finally, we found that ferroptosis inhibitor ferrostatin-1 prevented ferroptosis and suppressed SFTSV infection both <i>in vitro</i> and <i>in vivo</i> models. In summary, our study demonstrated that SFTSV infection could induce ferroptosis in liver, and m6A modified AT<i>G</i>5 mediated ferritinophagy to facilitate this process. Targeting ferroptosis may serve as a potential therapy for the treatment of SFTS.<b>Abbreviations:</b> ATG5: autophagy related 5; Baf-A1: bafilomycin A₁; Fer-1: ferrostatin-1; Fe²⁺: ferrous iron; FTH1: ferritin heavy chain 1; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic - pyruvic transaminase; GSH: glutathione; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MDA: malondialdehyde; NCOA4: nuclear receptor coactivator 4; ROS: reactive oxygen species; SFTSV: severe fever with thrombocytopenia virus; SQSTM1/p62: sequestosome 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-14"},"PeriodicalIF":0.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058162","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}