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An in-depth understanding of the mechanisms underlying MI\/R injury is crucial for devising strategies to minimize myocardial damage and enhance patient survival. Here, it is discovered that during MI\/R, double-stranded DNA (dsDNA)-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signal accumulates, accompanied by high rates of myocardial ferroptosis. The specific deletion of\n                    <jats:italic>cgas<\/jats:italic>\n                    or\n                    <jats:italic>Sting<\/jats:italic>\n                    in cardiomyocytes, resulting in the inhibition of oxidative stress, has been shown to mitigate ferroptosis and I\/R injury. Conversely, activation of STING exacerbates ferroptosis and I\/R injury. Mechanistically, STING directly targets glutathione peroxidase 4 (GPX4) to facilitate its degradation through autophagy, by promoting the fusion of autophagosomes and lysosomes. This STING-GPX4 axis contributes to cardiomyocyte ferroptosis and forms a positive feedback circuit. Blocking the STING-GPX4 interaction through mutations in\n                    <jats:italic>T<\/jats:italic>\n                    267 of STING or\n                    <jats:italic>N<\/jats:italic>\n                    146 of GPX4 stabilizes GPX4. Therapeutically, AAV-mediated GPX4 administration alleviates ferroptosis induced by STING, resulting in enhanced cardiac functional recovery from MI\/R injury. Additionally, the inhibition of STING by H-151 stabilizes GPX4 to reverse GPX4-induced ferroptosis and alleviate MI\/R injury. Collectively, a novel autophagy-dependent ferroptosis mechanism is identified in this study. Specifically, STING autophagy induced by anoxia or ischemia-reperfusion leads to GPX4 degradation, thereby presenting a promising therapeutic target for heart diseases associated with I\/R.\n                  <\/jats:p>","DOI":"10.1038\/s41392-025-02216-9","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T19:01:39Z","timestamp":1745521299000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":179,"title":["STING aggravates ferroptosis-dependent myocardial ischemia-reperfusion injury by targeting GPX4 for autophagic degradation"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6515-7621","authenticated-orcid":false,"given":"Xiaohong","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sizhe","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2782-1592","authenticated-orcid":false,"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangyu","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changhao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenghu","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiming","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqian","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghao","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiqing","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhai","family":"Sui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haonan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4432-6144","authenticated-orcid":false,"given":"Yun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3672-6543","authenticated-orcid":false,"given":"Cheng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"2216_CR1","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1038\/s41569-020-0403-y","volume":"17","author":"G Heusch","year":"2020","unstructured":"Heusch, G. Myocardial ischaemia-reperfusion injury and cardioprotection in perspective. Nat. Rev. Cardiol. 17, 773\u2013789 (2020).","journal-title":"Nat. Rev. Cardiol."},{"key":"2216_CR2","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.medj.2023.12.007","volume":"5","author":"G Heusch","year":"2024","unstructured":"Heusch, G. Myocardial ischemia\/reperfusion: Translational pathophysiology of ischemic heart disease. Medicine 5, 10\u201331 (2024).","journal-title":"Medicine"},{"key":"2216_CR3","doi-asserted-by":"publisher","first-page":"3052","DOI":"10.7150\/thno.54113","volume":"11","author":"X Wu","year":"2021","unstructured":"Wu, X., Li, Y., Zhang, S. & Zhou, X. Ferroptosis as a novel therapeutic target for cardiovascular disease. 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