Autophagy最新文献

{"title":"Targeted genome editing of ZKSCAN3 mitigates the neurotoxicity caused by mutant HTT (huntingtin) in a Huntington disease animal model and three-dimensional cell culture of Huntington disease.","authors":"Hyun Jung Park, JiYeon Kim, Jiwoo Choi, Chongsuk Ryou, Eunji Shin, Jae Young Lee","doi":"10.1080/15548627.2025.2569965","DOIUrl":"https://doi.org/10.1080/15548627.2025.2569965","url":null,"abstract":"<p><p>Huntington disease (HD) is a neurodegenerative disease caused by the expression of a mutant form of HTT (huntingtin; mHTT), caused by an abnormal expansion of polyglutamine in HTT. In HD, macroautophagy/autophagy dysfunction can cause mHTT accumulation. Moreover, the promotion of autophagy is considered a therapeutic strategy for the treatment of HD. ZKSCAN3 (zinc finger with KRAB And SCAN domains 3) has been identified as a transcriptional repressor of TFEB (transcription factor EB), a master regulator of autophagy and lysosomal functions. In this study, we conducted CRISPR-Cas9-based gene ablation to disrupt ZKSCAN3 in HD animal models and HD patient-induced pluripotent stem cell (iPSC) -derived three-dimensional (3D) spheroids. In animal models of HD, targeted in vivo <i>zkscan3</i> ablation via a single adeno-associated virus (AAV) mediated CRISPR-Cas9 approach resulted in reduced mHTT levels, leading to improvements in both behavioral symptoms and the brain environment. Furthermore, CRISPR-Cas9 mediated ablation of ZKSCAN3 in 3D spheroids from HD patient-derived iPSC resulted in increased autophagy and lysosomal function, along with reduced mHTT accumulation. Specifically, in iPSC-derived neurons from HD patients, ZKSCAN3-depleted neurons demonstrated increased lysosomal function and reduced oxidative stress compared to controls. Additionally, transcriptional analysis of ZKSCAN3-edited neurons revealed an increased expression of genes involved in synaptic function and transporter activity. Taken together, these results suggest that in HD treatment strategies for improving neuronal function and the brain environment, ZKSCAN3 downregulation in neurons by autophagy activation may improve the brain environment through neuronal self-repair.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214755","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-dependent proteostasis suppresses breast cancer metastasis.","authors":"Jayanta Debnath, Gourish Mondal","doi":"10.1080/15548627.2025.2569677","DOIUrl":"https://doi.org/10.1080/15548627.2025.2569677","url":null,"abstract":"<p><p>In breast cancer, macroautophagy/autophagy suppresses key steps of the metastatic cascade, including colonization and outgrowth at distant sites. However, the molecular mechanisms behind this suppression have remained unclear. Our recent study shows that increased metastasis observed in the setting of autophagy deficiency is driven by the accumulation of phase-separated biomolecular condensates containing the autophagy cargo receptors NBR1 and SQSTM1. These NBR1-SQSTM1 condensates sequester ITCH, an E3 ubiquitin ligase responsible for degrading TP63, a transcription factor that promotes basal differentiation. Hence, ITCH sequestration stabilizes and activates TP63 in breast cancer cells, hence promoting an aggressive, pro-metastatic basal-like differentiation state. Overall, our findings suggest that the potential benefits of targeting autophagy in cancer therapy are accompanied by defects in proteostasis, which disrupts epithelial lineage fidelity and enhances metastatic potential. We propose that targeting NBR1-SQSTM1 condensates may offer new therapeutic avenues to prevent metastasis, particularly in the context of autophagy deficiency.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214764","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":"Aging-rewired metabolic cues promote autophagy and senescence via DRAM1.","authors":"Jinghong Yang, Haobin Sun, Keqing Xu, Xiaomei Zhang, Mudan Huang, Guanghui Jin, Yasong Liu, Weizhao Chen, Shunan Lin, Juan Shen, Chuan-Qi Zhong, Yan Xu, Qi Zhang, Wei Liu, Yang Yang, Jingxing Ou","doi":"10.1080/15548627.2025.2568487","DOIUrl":"https://doi.org/10.1080/15548627.2025.2568487","url":null,"abstract":"<p><p>Being a major contributor to cell senescence and aging, DNA damage activates macroautophagy/autophagy, but how this process is affected by aging-rewired metabolism in normal biological systems remains to be explored. Here in cultured human umbilical cord-derived mesenchymal stem cells (HsMSCs) and the mouse liver that accumulate DNA damage during aging, we found an elevation of DRAM1 (DNA damage regulated autophagy modulator 1) and DRAM1-mediated pro-senescent autophagy (DMPA). Confirming that DRAM1 activated AMPK, we sought DMPA-associated metabolic features and noted substantial enrichment of N-acetylhistamine (N-AcHA) and phosphatidylethanolamine (PE) products in the aging HsMSCs and mouse liver. Elevating DNA damage and senescence, N-AcHA supplements were sufficient to upregulate DRAM1 and DMPA in primary hepatocytes from young mice but not even in pre-senescent HsMSCs, hence reflecting the differential tolerance of these cell models toward cytotoxic metabolic cues. The effects of N-AcHA were further verified in mouse aging and post-hepatectomy liver regeneration models. In contrast, accumulating cellular PE contents via ethanolamine supplements augmented autophagy but not DNA damage and senescence despite tending to induce DRAM1. Combined treatments with N-AcHA and ethanolamine were sufficient to trigger DMPA in HsMSCs. Despite their differential cellular responses toward N-AcHA and ethanolamine supplements, in primary HsMSCs and mouse hepatocytes DMPA did not notably downregulate SQSTM1/p62 proteins, which differed from general macroautophagy and may constitutively support the fusion of SQSTM1-modified cargo-containing autophagosomes with lysosomes. Overall, this study reveals DMPA-promoting metabolic and molecular features. Thus, targeting certain metabolic pathways and DMPA may promote DNA repair and delay senescence/aging.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214587","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":"Mitophagy-mediated S1P facilitates muscle adaptive responses to endurance exercise through SPHK1-S1PR1/S1PR2 in slow-twitch myofibers.","authors":"Minghong Leng, Fenghe Yang, Junhui Zhao, Yufei Xiong, Yiqing Zhou, Mingyang Zhao, Shi Jia, Limei Liu, Qiaoxia Zheng, Lebin Gan, Jingjing Ye, Ming Zheng","doi":"10.1080/15548627.2025.2488563","DOIUrl":"10.1080/15548627.2025.2488563","url":null,"abstract":"<p><p>Endurance exercise triggers adaptive responses especially in slow-twitch myofibers of skeletal muscles, leading to the remodeling of myofiber structure and the mitochondrial network. However, molecular mechanisms underlying these adaptive responses, with a focus on the fiber type-specific perspective, remains largely unknown. In this study we analyzed the alterations of transcriptomics and metabolomics in distinct skeletal myofibers in response to endurance exercise. We determined that genes associated with sphingolipid metabolism, namely those encoding SPHK1, S1PR1, and S1PR2, are enriched in slow-twitch but not fast-twitch myofibers from both mouse and human skeletal muscles, and found that the SPHK1-S1PR pathway is essential for adaptive responses of slow-twitch to endurance exercise. Importantly, we demonstrate that endurance exercise causes the accumulation of ceramides on stressed mitochondria, and the mitophagic degradation of ceramides results in an increase of the sphingosine-1-phosphate (S1P) level. The elevated S1P thereby facilitates mitochondrial adaptation and enhances endurance capacity via the SPHK1-S1PR1/S1PR2 axis in slow-twitch muscles. Moreover, administration of S1P improves endurance performance in muscle atrophy mice by emulating these adaptive responses. Our findings reveal that the SPHK1-S1P-S1PR1/S1PR2 axis through mitophagic degradation of ceramides in slow-twitch myofibers is the central mediator to endurance exercise and highlight a potential therapeutic target for ameliorating muscle atrophy diseases.<b>Abbreviations</b> CQ: chloroquine; DMD: Duchenne muscular dystrophy; EDL: extensor digitorum longus; FCCP: carbonyl cyanide p-trifluoromethoxyphenyl hydrazone; FUNDC1: FUN14 domain containing 1; GTEx: genotype-tissue expression; MYH: myosin heavy chain; mtDNA: mitochondrial DNA; PPARGC1A/PGC-1α: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; RG: red gastrocnemius; S1P: sphingosine-1-phosphate; S1PR: sphingosine-1-phosphate receptor; Sol: soleus; SPHK1: sphingosine kinase 1; TA: tibialis anterior; WG: white gastrocnemius.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2111-2129"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual roles of CXCR4 (C-X-C motif chemokine receptor 4) in promoting entry of ebolavirus and targeting excessive glycoprotein for reticulophagic degradation to facilitate viral fitness.","authors":"Hongxin Huang, Wendi Shi, Huijun Yan, Linjin Fan, Jiajun Lu, Zhenyu Long, Xiaowei Li, Jiao Li, Jie Wang, Linna Liu, Jun Qian","doi":"10.1080/15548627.2025.2492877","DOIUrl":"10.1080/15548627.2025.2492877","url":null,"abstract":"<p><p>Ebola virus disease (EVD) caused by <i>Zaire</i> Ebolavirus (EBOV) infection is a major threat to public health in Africa and even worldwide, due to its extremely high mortality rate. However, there are still no effective antiviral therapies that can completely cure EVD. A comprehensive understanding of virus-host interactions would be beneficial for developing new antiviral agents. Here, we showed that CXCR4-induced macroautophagy/autophagy and was internalized to endosomes by interacting with glycoprotein (GP) on viral particles during EBOV infection; this promoted the EBOV attachment and entry, which was reduced by CXCR4 antagonist and neutralizing antibody. We also found that CXCR4 increased EBOV replication by downregulating cytotoxic GP to promote viral fitness instead of influencing the assembly of viral factory. Mechanistically, excessive EBOV GP could hijack CXCR4 sorting and transporting pathways by their interactions with HGS, one of the key components of the ESCRT machinery; subsequently GP could be carried back to the endoplasmic reticulum by CXCR4, where the E3 ubiquitin ligase RNF185 was recruited to polyubiquitinate GP in a K27- and K63-linked manner. Finally, polyubiquitinated GP was degraded in lysosomes <i>via</i> reticulophagy by interacting with RETREG1 (reticulophagy regulator 1), in an ATG3- and ATG5-dependent manner. Our findings revealed dual roles of CXCR4 in regulation of EBOV life cycle, either acting as an entry factor by interacting with GP on viral particles to facilitate viral entry or targeting excessive GP for reticulophagic degradation, providing new evidence that EBOV hijacked the host vesicular transportation system through efficient virus-host interactions to facilitate viral fitness.<b>Abbreviations:</b> Baf A1: bafilomycin A₁; BDBV: <i>Bundibugyo</i> Ebolavirus; CHX: cycloheximide; CXCR4: C-X-C motif chemokine receptor 4; CLEC4M/DC-SIGNR: C type lectin domain family 4 member M; EBOV: <i>Zaire</i> Ebolavirus; EEA1: early endosome antigen 1; ER: endoplasmic reticulum; ERAD: ER-associated degradation; ESCRT: endosomal sorting complex required for transport; EVD: Ebolavirus disease; HAVCR1/TIM-1: hepatitis A virus cellular receptor 1; GP: glycoprotein; HGS: hepatocyte growth factor-regulated tyrosine kinase substrate; HIV: human immunodeficiency virus; IFL: internal fusion loop; ITCH/AIP4: itchy E3 ubiquitin protein ligase; LAMP: lysosomal associated membrane protein; LC-MS/MS: liquid chromatography mass spectrometry; PDIs: protein disulfide isomerases; RBD: receptor binding domain; RESTV: <i>Reston</i> Ebolavirus; RETREG1: reticulophagy regulator 1; RNF185: ring finger protein 185; SQSTM1/p62: sequestosome 1; SUDV: <i>Sudan</i> Ebolavirus; TAFV: <i>Taï Forest</i> Ebolavirus; TRIM21: tripartite motif containing 21; trVLPs: transcription- and replication-competent virus-like particles; Ub: ubiquitin.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2148-2167"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutralization of the autophagy-repressive tissue hormone DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) for the treatment of hepatocellular carcinoma.","authors":"Sijing Li, Flavia Lambertucci, Isabelle Martins, Jonathan Pol, Maria Chiara Maiuri, Guido Kroemer","doi":"10.1080/15548627.2025.2545472","DOIUrl":"10.1080/15548627.2025.2545472","url":null,"abstract":"<p><p>DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein), which is a major macroautophagy/autophagy-repressive protein, is emerging as a key player in hepatocellular carcinoma (HCC) pathogenesis through multifaceted roles that encompass both cell-intrinsic and -extrinsic mechanisms. Beyond promoting cancer cell proliferation, DBI/ACBP contributes to a pro-tumorigenic microenvironment by sustaining inflammation and impairing immunosurveillance. Experimental models of HCC, whether induced by oncogenes, hepatotoxins, or diet, consistently reveal that hepatocyte-specific knockout of <i>DBI</i>, systemic mutation of the DBI/ACBP receptor, which is GABRG2 (gamma-aminobutyric acid type A receptor subunit gamma2), or antibody-mediated neutralization of DBI/ACBP attenuates tumor growth. Mechanistically, DBI/ACBP inhibition reduces fibrogenesis, and the accumulation of immunosuppressive T-cell subtypes while enhancing antitumor immune responses in the context of PDCD1/PD-1 blockade. Simultaneously, DBI/ACBP inhibition increases the expression of pro-ferroptotic genes and proteins while decreasing those that are anti-ferroptotic in the liver, thereby sensitizing HCC cells to ferroptosis- a form of cell death associated with autophagy. Clinically, elevated <i>DBI</i> mRNA expression in tumors and circulating DBI/ACBP protein correlate with poor prognosis in HCC patients. Hence, targeting DBI/ACBP offers a promising strategy to disrupt the metabolic, inflammatory, and immunosuppressive networks driving HCC progression.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2301-2303"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy inhibition in LGALS9-overexpressing nasopharyngeal carcinoma unleashes immune response.","authors":"Clarence Pascual, Daniel J Klionsky","doi":"10.1080/15548627.2025.2534072","DOIUrl":"10.1080/15548627.2025.2534072","url":null,"abstract":"<p><p>When cells within our bodies begin to exhibit tumor-specific antigens, a specialized group of immune cells, known as immune effector cells, plays a crucial role in mounting both innate and adaptive immune responses. Cancer cells are notorious for developing strategies to hide from, suppress, and manipulate the immune system, collectively known as immune evasion. In the paper by Kam et al. the authors propose that intratumoral cell-associated, as opposed to secreted, LGALS9 (galectin 9) suppresses the activation of cytotoxic T lymphocytes in a macroautophagy/autophagy-dependent manner in nasopharyngeal carcinoma (NPC) cell lines.<b>Abbreviations</b>: CTL: cytotoxic T lymphocyte; NPC: nasopharyngeal carcinoma.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2089-2090"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stage-specific regulation by autophagy-related transcription factors drives hematopoietic stem cell formation.","authors":"Jia Chen, Jiayi Zheng, Xiaoya Chen, Gangjue Tang, Yan Huang","doi":"10.1080/15548627.2025.2551671","DOIUrl":"10.1080/15548627.2025.2551671","url":null,"abstract":"<p><p>Macroautophagy/autophagy critically regulates hematopoietic stem cell (HSC) development and differentiation, yet the upstream transcriptional mechanisms governing autophagy during dynamic developmental processes remain poorly characterized. Here, we combined single-cell RNA sequencing (scRNA-seq) with metaTF to dissect six consecutive stages of murine HSC development, spanning the aorta-gonad-mesonephros (AGM) region at embryonic day (E) 10.5, the fetal liver at E12.5/E14.5, and adult bone marrow. Beyond transcript abundance alone, we found that the activity of autophagy-related transcription factors (TFs) more robustly characterized cell-type specificity, particularly distinguishing T1 and T2 pre-HSCs, and identified 32 cell-type-specific autophagy-related TFs. Stage-specific autophagy-related TF-target gene networks constructed for T1 and T2 revealed functional partitioning of the pre-HSC stage: an early T1 phase characterized by elevated autophagy activity, and a later T2 phase primarily involved in proliferation and maturation. These findings highlight the temporal regulation exerted by autophagy-related TFs during embryonic hematopoiesis and underscore the importance of autophagy in stem cell fate decision.<b>Abbreviations:</b> HSC: hematopoietic stem cell; TF: transcription factor.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2307-2309"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982314","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":"Statement of Retraction: Autophagic proteins regulate cigarette smoke induced apoptosis: Protective role of heme oxygenase-1.","authors":"","doi":"10.1080/15548627.2024.2343270","DOIUrl":"10.1080/15548627.2024.2343270","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"iii"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140869085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of PINK1 senses ROS signaling to facilitate neuroblastoma cell pyroptosis.","authors":"Yuyuan Zhu, Min Cao, Yancheng Tang, Yifan Liu, Haiji Wang, Jiaqi Qi, Cainian Huang, Chenghao Yan, Xu Liu, Sijia Jiang, Yufei Luo, Shaogui Wang, Bo Zhou, Haodong Xu, Ying-Ying Lu, Liming Wang","doi":"10.1080/15548627.2025.2487037","DOIUrl":"10.1080/15548627.2025.2487037","url":null,"abstract":"<p><p>Mitochondria serve as the primary source of intracellular reactive oxygen species (ROS), which play a critical role in orchestrating cell death pathways such as pyroptosis in various types of cancers. PINK1-mediated mitophagy effectively removes damaged mitochondria and reduces detrimental ROS levels, thereby promoting cell survival. However, the regulation of pyroptosis by PINK1 and ROS in neuroblastoma remains unclear. In this study, we demonstrate that inhibition or deficiency of PINK1 sensitizes ROS signaling and promotes pyroptosis in neuroblastoma cells via the BAX-caspase-GSDME signaling pathway. Specifically, inhibition of PINK1 by AC220 or knockout of <i>PINK1</i> impairs mitophagy and enhances ROS production, leading to oxidation and oligomerization of TOMM20, followed by mitochondrial recruitment and activation of BAX. Activated BAX facilitates the release of CYCS (cytochrome c, somatic) from the mitochondria into the cytosol, activating CASP3 (caspase 3). Subsequently, activated CASP3 cleaves and activates GSDME, inducing pyroptosis. Furthermore, inhibition or deficiency of PINK1 potentiates the anti-tumor effects of the clinical ROS-inducing drug ethacrynic acid (EA) to inhibit neuroblastoma progression <i>in vivo</i>. Therefore, our study provides a promising intervention strategy for neuroblastoma through the induction of pyroptosis.<b>Abbreviation:</b> AC220, quizartinib; ANOVA, analysis of variance; ANXA5, annexin A5; BAX, BCL2 associated X, apoptosis regulator; BAK1, BCL2 antagonist/killer 1; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; COX4/COX IV, cytochrome c oxidase subunit 4; CS, citrate synthase; CSC, cancer stem cell; CYCS, cytochrome c, somatic; DTT, dithiothreitol; DNA, deoxyribonucleic acid; EA, ethacrynic acid; Fer-1, ferroptosis inhibitor ferrostatin-1; FLT3, fms related tyrosine kinase 3; GSDMD, gasdermin D; GSDME, gasdermin E; kDa, kilodalton; LDH, lactate dehydrogenase; MFN1, mitofusin 1; MFN2, mitofusin 2; mito, mitochondria; mito-ROS, mitochondrial ROS; mtKeima, mitochondria-targeted monomeric keima-red; ml, microliter; MT-CO2, mitochondrially encoded cytochrome c oxidase II; NAC, antioxidant N-acetyl-L-cysteine; Nec-1, necroptosis inhibitor necrostatin-1; OMA1, OMA1 zinc metallopeptidase; OMM, outer mitochondrial membrane; PARP, poly(ADP-ribose) polymerase; PBS, phosphate-buffered saline; PI, propidium iodide; PINK1, PTEN induced kinase 1; PRKN/Parkin, parkin RBR E3 ubiquitin protein ligase; Q-VD, Q-VD-OPH; ROS, reactive oxygen species; sg, single guide; sh, short hairpin; STS, staurosporine; TOMM20, translocase of outer mitochondrial membrane 20; TIMM23, translocase of inner mitochondrial membrane 23; μm, micrometer; μM, micromolar.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2091-2110"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}