Complement system: A key player in hepatic ischemia-reperfusion injury

Hepatic ischemia-reperfusion injury (IRI) represents a major challenge in liver surgery and transplantation, as the restoration of blood flow to previously ischemic tissue paradoxically exacerbates cellular and vascular damage. A growing body of evidence highlights the complement system as a central mediator in this process, linking sterile inflammation to hepatocellular dysfunction and microvascular impairment. Upon activation by damage-associated molecular patterns (DAMPs), complement triggers the generation of potent effector molecules such as C3a, C5a, and the membrane attack complex (MAC), which together amplify immune cell recruitment, cytokine release, oxidative stress, and endothelial disruption. This review provides a detailed analysis of the mechanistic role of complement in hepatic IRI and discusses current experimental and translational strategies aimed at modulating this pathway. Particular focus is given to targeted approaches including C5 inhibitors, C5aR1 antagonists, upstream C3 inhibitors and recombinant regulatory proteins. While these interventions have shown promise in preclinical models, the dual role of complement in both injury propagation and tissue regeneration highlights the need for finely tuned therapeutic modulation. Understanding these mechanisms is essential to harness complement-targeted therapies that reduce liver injury without compromising immune competence or regenerative potential.