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However, fast and accurate identification, as well as the targeted protection of injured cardiomyocytes following ischemia\/reperfusion (I\/R)\u00a0injury, remain significantly challenging. Here, a near infrared heptamethine dye IR\u2010780 is shown that has the potential to quickly monitor the area at risk following I\/R injury by selectively entering the cardiomyocytes of the at\u2010risk heart tissues. Preconditioning with IR\u2010780 or timely IR\u2010780 administration before reperfusion significantly protects the heart from ischemia and oxidative stress\u2010induced cell death, myocardial remodeling, and heart failure in both rat and pig models. Furthermore, IR\u2010780 can directly bind to F0F1\u2010ATP synthase of cardiomyocytes, rapidly decrease the mitochondrial membrane potential, and subsequently slow down the mitochondrial energy metabolism, which induces the mitochondria into a \u201cquiescent state\u201d and results in mitochondrial permeability transition pore inhibition by preventing mitochondrial calcium overload. Collectively, the findings show the feasibility of IR\u2010780\u2010based imaging and protection strategy for I\/R injury in a preclinical context and indicate that moderate mitochondrial function depression is a mode of action that can be targeted in the development of cardioprotective reagents.<\/jats:p>","DOI":"10.1002\/advs.202307880","type":"journal-article","created":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T05:47:17Z","timestamp":1702532837000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Pharmaceutical Manipulation of Mitochondrial F0F1\u2010ATP Synthase Enables Imaging and Protection of Myocardial Ischemia\/Reperfusion Injury Through Stress\u2010induced Selective Enrichment"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9726-0161","authenticated-orcid":false,"given":"Zelin","family":"Chen","sequence":"first","affiliation":[{"name":"Institute of Rocket 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