Myocardial ischemia-reperfusion injury (MIRI) is a major complication of reperfusion therapy for acute myocardial infarction. It severely limits the clinical efficacy of such treatments and leads to adverse outcomes, including heart failure. The pathological process of MIRI involves a complex molecular network formed by oxidative stress, calcium overload, inflammatory responses, and mitochondrial dysfunction. These processes ultimately converge to trigger irreversible cardiomyocyte death. Apoptosis and necrosis have traditionally been considered the primary forms of cell death. However, recent studies indicate that novel types of regulated cell death-such as ferroptosis, necroptosis, pyroptosis, and cuproptosis-play crucial, and sometimes dominant, roles in MIRI. These cell death pathways do not operate in isolation. They share upstream triggers (e.g., reactive oxygen species, calcium signals) and exhibit extensive "crosstalk" at the molecular level. This interplay forms a dynamic and interactive multimodal death network that collectively determines the fate of cardiomyocytes. This review systematically elaborates on the core molecular mechanisms and key regulatory molecules of various regulated cell death types in MIRI, including apoptosis, necroptosis, ferroptosis, pyroptosis and cuproptosis. Furthermore, we discuss the complex regulatory network, highlighting how autophagy acts as a dual-function pathway that can either protect cardiomyocytes or, when dysfunctional, contribute to cell death and interact with other RCD modalities. Furthermore, the review critically assesses potential therapeutic strategies targeting these death pathways. These include specific inhibitors (e.g., Ferrostatin-1, Necrostatin-1), naturally active compounds, and emerging approaches like nanotechnology, gene therapy, and non-pharmacological interventions (e.g., ischemic preconditioning). The research progress and translational prospects of these strategies are highlighted. Despite challenges related to pathological complexity, temporal dynamics, and clinical translation, a deeper understanding of the cell death network and the development of innovative, multi-target, synergistic therapies will pave new avenues for ultimately overcoming the clinical challenge of MIRI.
