Regulated cell death in ischemia-reperfusion injury of skin flaps: from molecular mechanism to remote ischemic preconditioning

Abstract

Background and objective. Ischemia-reperfusion injury (IRI) is a frequent cause of flap necrosis and failure, and regulated cell death is increasingly implicated in this damage. The objective was to synthesize the regulated cell death modalities involved in skin flap IRI and the conditioning strategies, especially remote ischemic preconditioning (RIPC), that modulate them. Methods. Narrative review with structured search in five databases (2015–2026; Spanish and English), with transparency reporting based on the PRISMA 2020 framework and quality verification using the SANRA criteria. Primary experimental and clinical studies on regulated cell death and/or flap conditioning were included. Results. Eleven studies were included: three clinical and eight preclinical. Apoptosis, necroptosis, and pyroptosis participate in flap loss, and their modulation improves survival in preclinical models. In clinical trials, remote ischemic preconditioning (CPR) and remote ischemic conditioning (ICR) did not improve survival or flap oxygenation and did not reduce oxidative stress; the RIPC only selectively modulated apoptosis and necroptosis. Conclusions. Modulation of regulated cell death is a promising preclinical target; clinical evidence for CPRI/IQR is limited and, in the flap, outcomes assessed, showed no benefit. Ferropttosis and PANoptosis do not have sufficient evidence in this context. Clinical trials with survival outcomes are required.