Connexin 43 (Cx43) serves as the fundamental component of gap junctions in cardiomyocytes, facilitating intercellular electrical signal transmission and metabolic coupling. It plays a crucial role in maintaining cardiac electrophysiological stability. The expression, subcellular localization, and functional state of Cx43 are regulated by a variety of post-translational modifications, such as phosphorylation, glycosylation, acetylation, ubiquitination, and S-nitrosylation.During myocardial ischemia-reperfusion injury, Cx43 undergoes dephosphorylation during the ischemic phase, leading to gap junction uncoupling. Upon reperfusion, oxidative stress accelerates Cx43 degradation and induces abnormal opening of hemichannels, thereby exacerbating ion imbalance, calcium overload, and oxidative damage, which ultimately contribute to arrhythmias and cardiomyocyte apoptosis. Moreover, Cx43 exhibits cardioprotective potential under specific subcellular localization (e.g., in mitochondria) and particular modification states. This review systematically summarizes the biological characteristics and post-translational modifications of Cx43, and evaluates its multifaceted mechanisms in myocardial ischemia-reperfusion injury through the regulation of electro-metabolic coupling, as well as its potential as a therapeutic target.