Myocardial Ischemia-Reperfusion Injury: Molecular Mechanisms and Innovative Therapeutic Strategies

Myocardial ischemia–reperfusion injury (MIRI) is a critical pathological paradox following revascularization in acute myocardial infarction, yet effective clinical interventions remain limited. MIRI involves a complex, interlinked hierarchy of programmed cell death modalities, including ferroptosis, pyroptosis, and cuproptosis, which form a network mediated by the stimulator of interferon genes–glutathione peroxidase 4 (STING–GPX4), NOD-like receptor pyrin domain containing 3–gasdermin D (NLRP3–GSDMD), and sirtuin 3–ATPase copper transporting alpha (SIRT3–ATP7A) axes. The dynamic evolution of the immune microenvironment, mitochondrial dysfunction, and non-coding RNA regulatory networks further compound this. Emerging strategies, including bionanotechnology-enabled targeted delivery, intelligent responsive biomaterials, drug repurposing, genome editing, and precise ion channel modulation, demonstrate significant therapeutic potential. Despite bottlenecks in clinical translation related to delivery efficiency, patient heterogeneity, and efficacy evaluation, multidisciplinary integration and technological innovations are propelling a paradigm shift in MIRI treatment from revascularization alone to comprehensive myocardial protection.