Myocardial ischemia-reperfusion injury (MIRI) is an inevitable pathological complication following reperfusion therapy for acute myocardial infarction. Massive reactive oxygen species burst, mitochondrial dysfunction, inflammatory cascade activation and multiple programmed cell death jointly aggravate irreversible cardiomyocyte loss, expanding infarct size and increasing the risk of progressive heart failure. As conserved NAD⁺-dependent deacetylases, the seven-member sirtuin (SIRT1-SIRT7) family exert widespread cardioprotective effects against MIRI, yet the subtype-specific molecular mechanisms, coordinated regulatory networks and translational bottlenecks lack systematic collation in existing reviews. This review aims to systematically summarize the regulatory pathways of all SIRT isoforms governing oxidative stress, mitochondrial homeostasis, inflammatory response and programmed cell death under MIRI, compare divergent biological functions among subtypes, sort out available SIRT-targeted pharmacological intervention strategies, and further clarify major obstacles restricting clinical translation, as well as prospective therapeutic targets for subsequent research. Distinguished by subcellular localization, nuclear, cytoplasmic and mitochondrial SIRT members participate in multi-layered myocardial defense. Nuclear SIRT1 coordinates AMPK-FOXO3-Nrf2 signaling to upregulate antioxidant enzymes and maintain mitophagic balance; mitochondrial SIRT3 dominates PINK1/Parkin-dependent mitophagy and deacetylates SOD2 to eliminate mitochondrial reactive oxygen species; cytoplasmic SIRT2 alleviates endoplasmic reticulum stress and restrains NLRP3 inflammasome activation; mitochondrial SIRT4 and SIRT5 stabilize mitochondrial fusion dynamics and eliminate lipid peroxidation via lysine desuccinylation, respectively; nuclear SIRT6 and SIRT7 relieve reperfusion inflammation, repair oxidative DNA damage and block late myocardial fibrosis. Collectively, the whole SIRT family forms an integrated endogenous protective network targeting all core pathological links of MIRI. In conclusion, SIRT1, SIRT3 and SIRT6 act as core cardioprotective subtypes: they synergistically activate the AMPK/Nrf2 antioxidant axis to block reperfusion oxidative injury. SIRT2, SIRT4, SIRT5 and SIRT7 serve auxiliary regulatory roles by balancing cardiac energy metabolism and maintaining genomic integrity. Current SIRT small-molecule agonists face prominent translational limitations including low oral bioavailability and poor myocardial tissue selectivity. Mitochondria or cardiomyocyte-targeted nano-delivery systems provide a feasible strategy to overcome such defects. Large animal MIRI models and prospective human clinical trials are urgently required to validate the long-term safety and therapeutic efficacy of SIRT-targeted interventions before clinical transformation.
