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Currently, the role of STX12 in cardiovascular physiology remains unclear. Using zebrafish and mice, it is shown that STX12 loss leads to pericardial edema, cardiac malformations, and heart failure. <jats:italic>Stx12<\/jats:italic> depletion disrupts mitochondrial morphology, reduces iron and zinc levels, and impairs ATP production. <jats:italic>Stx12<\/jats:italic>\u2010deficient cardiomyocytes exhibit prolonged repolarization due to decreased sarcoplasmic reticulum Ca<jats:sup>2+<\/jats:sup>\u2010ATPase (SERCA) activity. Treatment with rapamycin, an mTOR inhibitor, restores mitochondrial protein expression and function by prompting the TFEB\u2010PGC1\u03b1 axis, enhances SERCA activity via the CAMKII\u2010phospholamban pathway, and reduces the expression of stress markers. These findings suggest that STX12 plays an important role in the energy metabolism and metal homeostasis of cardiomyocytes. Enhancing mitochondrial function, autophagy, and SERCA activity through the administration of rapamycin may provide a potential therapeutic approach for cardiomyopathies associated with STX12 deficiency and hypometabolism.<\/jats:p>","DOI":"10.1002\/advs.202507210","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T07:35:34Z","timestamp":1750923334000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Rapamycin Alleviates Heart Failure Caused by Mitochondrial Dysfunction and SERCA Hypoactivity in <i>Syntaxin 12\/13<\/i> Deficient Models"],"prefix":"10.1002","volume":"12","author":[{"given":"Run\u2010Zhou","family":"Yang","sequence":"first","affiliation":[{"name":"Clinical Systems Biology Laboratories The First Affiliated Hospital of Zhengzhou University  Zhengzhou 450052 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Shanghai General Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 200000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology School of Basic Medical Sciences Tianjin Medical University  Tianjin 300070 China"},{"name":"Department of Cardiology The First Affiliated Hospital of Zhengzhou University  Zhengzhou 450052 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu\u2010Ang","family":"Li","sequence":"additional","affiliation":[{"name":"Clinical Systems Biology Laboratories The First Affiliated Hospital of Zhengzhou University  Zhengzhou 450052 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan\u2010Hua","family":"Liu","sequence":"additional","affiliation":[{"name":"Clinical Systems Biology Laboratories The First Affiliated Hospital of Zhengzhou University  Zhengzhou 450052 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuanbin","family":"Wu","sequence":"additional","affiliation":[{"name":"Replatium Inc.  55 YuanZhong Road, PuDong New Area Shanghai 201300 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei\u2010Pei","family":"Liu","sequence":"additional","affiliation":[{"name":"Clinical Systems Biology Laboratories The First Affiliated Hospital of Zhengzhou University  Zhengzhou 450052 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenju","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Sciences and Technology Tongji University  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Biochemistry and Cell Biology Center for Excellence in Molecular Cell Science Chinese Academy of Sciences  Shanghai 200031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cizhong","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Life Sciences and Technology Tongji University  Shanghai 200092 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health Chinese Academy of Sciences  Shanghai 200031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology School of Basic Medical Sciences Tianjin Medical University  Tianjin 300070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2603-9718","authenticated-orcid":false,"given":"Jian\u2010Sheng","family":"Kang","sequence":"additional","affiliation":[{"name":"Clinical Systems Biology Laboratories The First Affiliated Hospital of Zhengzhou University  Zhengzhou 450052 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"e_1_2_9_1_1","first-page":"1161","volume":"85","author":"King M.","year":"2012","journal-title":"Am. 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