The study reviews the role of SUR2A in cardioprotection by regulating ATP-sensitive K+ (KATP) channels, which link cellular metabolism with membrane excitability. SUR2A is a regulatory subunit of the KATP channel and it is a rate-limiting factor in the channel formation and, consequently the levels of. SUR2A set up the number of assembled KATP channels in the sarcolemma. An increased number of fully assembled KATP channels protect cardiomyocytes from stress by optimizing KATP channel opening and catalyzing ATP production in the subsarcolemmal space as these channels include ATP-producing enzymes alongside SUR2A and Kir6.2 subunits. Increased fully-assembled channels enhance ATP levels, beneficial during ischemia. SUR2A expression is regulated by mechanisms such as AMPK, PI3K/Akt, ERK1/2, and intracellular NAD+/NADH and ATP levels. Various compounds can regulate SUR2A, with nicotinamide identified as a clinically viable and safe option for increasing SUR2A and providing cardioprotection. SUR2A-based cardioprotection is an effective and safe strategy for clinical application.