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Here, we report that flavin-containing monooxygenase 2 (FMO2) levels were markedly increased in CMs in both ex vivo and in vivo models of ischemic injury. Genetic deletion of\n                    <jats:italic>FMO2<\/jats:italic>\n                    resulted in reduced CM survival and enhanced cardiac dysfunction, whereas CM-specific\n                    <jats:italic>FMO2<\/jats:italic>\n                    overexpression conferred a protective effect in infarcted rat hearts. Mechanistically, FMO2 inhibited the activation of ER stress\u2013induced apoptotic proteins, including caspase 12 and C\/EBP homologous protein (CHOP), by downregulating the unfolded protein response pathway. Furthermore, we identified FMO2 as a chaperone that catalyzes disulfide bond formation in unfolded and misfolded proteins through its GVSG motif. GVSG-mutated FMO2 failed to catalyze disulfide bond formation and lost its protection against ER stress and CM death. Finally, we demonstrated the protective effect of FMO2 in a human induced pluripotent stem cell\u2013derived CM model. Collectively, this study highlights FMO2 as a key modulator of oxidative protein folding in CMs and underscores its therapeutic potential for treating ischemic heart disease.\n                  <\/jats:p>","DOI":"10.1172\/jci177077","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T12:00:43Z","timestamp":1730376043000},"source":"Crossref","is-referenced-by-count":12,"title":["Flavin-containing monooxygenase 2 confers cardioprotection in ischemia models through its disulfide bond catalytic activity"],"prefix":"10.1172","volume":"134","author":[{"given":"Qingnian","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China."},{"name":"Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiniu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China."},{"name":"Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China."},{"name":"Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China."},{"name":"Cardiovascular Key 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