Cell death in ischemia-reperfusion injury: beyond a single-cell-death perspective

Ischemia-reperfusion injury (IRI) contributes to the pathogenesis of major diseases, including acute kidney injury, stroke, and myocardial infarction. Multiple forms of cell death, including apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis, are key contributors to IRI. The interplay among these cell-death programs adds to the complexity of the IRI landscape. Cell-death patterns differ markedly between the ischemic and reperfusion phases and across organs, reflecting the spatiotemporal and organ-specific features of IRI. Given the complex molecular mechanisms underlying IRI, multi-target small-molecule drugs, combination regimens, and nanodelivery systems have been explored, although most remain at the preclinical stage. In this review, we summarize the major cell-death modalities involved in IRI, their interconnected molecular targets and signaling pathways, and their phase-specific and organ-specific regulation. We further discuss the coordinated roles of non-coding RNAs, metabolic reprogramming, and epigenetic alterations in regulating cell death, as well as their therapeutic potential. Finally, we propose therapeutic strategies aimed at modulating crosstalk among cell-death modalities, with potential implications for individualized IRI therapy.