Narrative review discusses ischemia-reperfusion injury mechanisms and future therapeutic strategies.

Ischemia-reperfusion injury (IRI) represents a critical pathological process contributing to secondary tissue damage in cardiovascular and cerebrovascular diseases. The complexity of the cell death network involved poses substantial challenges for therapeutic intervention. Among emerging forms of regulated cell death, autophagy-dependent ferroptosis and PANoptosis have attracted considerable attention. This review aims to elucidate the potential formation of a highly coordinated cell death network in myocardial and cerebral IRI through the convergence of these two pathways via shared key molecules. By examining their molecular underpinnings, we focus on core regulators such as NLRP3, STING, RIPK, GPX4, and NCOA4, which not only drive their respective pathways but may also facilitate PANoptosome assembly and integrate death signals, thereby mediating signal amplification and crosstalk. Despite inherent differences between cardiac and cerebral tissues, this network may exert synergistic effects during IRI progression by sharing upstream oxidative stress and inflammatory signals. Although current evidence is largely derived from in vitro models, the in vivo interactions and clinical translational potential of these mechanisms remain to be further validated. We propose that future therapeutic strategies may shift from targeting individual pathways to intervening at critical crosstalk nodes, offering a new direction for developing more effective protective strategies against IRI in the heart, brain, and beyond.