Targeting ferroptosis and mitochondrial ROS: organoprotective mechanisms of anesthetic conditioning in liver transplantation
TL;DR
Ferroptosis and mitochondrial ROS provide a cohesive mechanistic framework for graft vulnerability at reperfusion and underscores the need for targeted mechanistic validation to translate anesthetic conditioning into effective clinical organ protection.
Abstract
Liver transplantation is the definitive treatment for advanced liver failure, yet ischemia-reperfusion injury (IRI) remains a major challenge—particularly for marginal, steatotic, or donation-after-circulatory-death (DCD) grafts. While oxidative stress and inflammation are long-recognized contributors to IRI, this review focuses on two tightly linked, mechanistically specific pathways: ferroptosis and mitochondrial reactive oxygen species (ROS). Together, these pathways convert reperfusion-associated metabolic stress into injury of hepatocytes, endothelium, and bile ducts. Anesthetic preconditioning has gained interest as a modulator of this injury cascade. Volatile anesthetics, alongside propofol and dexmedetomidine, show experimental efficacy in reducing IRI by stabilizing mitochondria, regulating redox status, preserving GPX4(Glutathione Peroxidase 4)/SLC7A11(Solute Carrier Family 7 Member 11)-mediated antioxidant capacity, limiting lipid peroxidation, and dampening innate immune responses. However, clinical translation is limited by heterogeneity in experimental models, variability in anesthetic regimens, overreliance on non-specific oxidative stress markers, and a lack of validated ferroptosis-related endpoints in human studies. In summary, ferroptosis and mitochondrial ROS provide a cohesive mechanistic framework for graft vulnerability at reperfusion. To advance this field, future clinical studies should move beyond general oxidative stress assessments toward biomarker-driven approaches—integrating ferroptosis-specific markers and mitochondrial function tests. Coupling these with risk stratification of donor livers based on biochemical profiles, and tracking clinically meaningful outcomes, will enable precision strategies to mitigate IRI. This review underscores the need for targeted mechanistic validation to translate anesthetic conditioning into effective clinical organ protection.