Functional relevance and mechanisms of necroptosis in ischemia–reperfusion injury

Abstract

Ischemia–reperfusion injury remains a major cause of mortality and disability worldwide, with limited therapeutic options. While reperfusion is essential for tissue salvage, it paradoxically triggers secondary damage, highlighting the need to better understand regulated cell death pathways. Traditionally, apoptosis was considered the dominant mechanism; however, incomplete protection by caspase inhibition revealed a substantial contribution of caspase‑independent death. Among these, necroptosis has emerged as a functionally purposeful process, eliminating compromised cells but simultaneously amplifying sterile inflammation through the release of damage‑associated molecular patterns. This review synthesizes current knowledge of necroptosis in ischemia–reperfusion injury. We first establish its functional relevance, then examine canonical and non‑canonical molecular pathways, including RIPK1–RIPK3–MLKL signaling, mitochondrial dysfunction, and CaMKIIδ‑mediated execution. We discuss mechanisms of CASP8 checkpoint weakening and bypass, emphasizing the roles of metabolic collapse, oxidative stress, and ZBP1‑mediated signaling. Finally, we highlight the cell‑type and temporal dynamics of necroptosis, as well as its translational implications. Recognizing necroptosis as a context‑dependent permissive state rather than a simple backup pathway provides a more comprehensive framework for understanding ischemic cell death and its tissue‑specific manifestations.