Targeting Ferroptosis and Mitochondrial ROS in Liver Transplantation

Liver transplantation serves as the definitive treatment for advanced liver failure, yet ischemia-reperfusion injury (IRI) remains a persistent barrier to successful outcomes. This challenge is especially pronounced in marginal, steatotic, or donation-after-circulatory-death grafts. While oxidative stress and inflammation are well-established contributors to IRI, recent mechanistic insights focus on two specific pathways: ferroptosis and mitochondrial reactive oxygen species (ROS). These processes convert metabolic stress during reperfusion into cellular injury across hepatocytes, endothelium, and bile ducts.

Anesthetic preconditioning has emerged as a potential modulator of this injury cascade. Volatile anesthetics, alongside propofol and dexmedetomidine, demonstrate experimental efficacy in reducing IRI through multiple mechanisms. These agents stabilize mitochondria, regulate redox status, and preserve GPX4/SLC7A11-mediated antioxidant capacity. By limiting lipid peroxidation and dampening innate immune responses, they may mitigate the cascade of cellular damage associated with reperfusion.

The authors argue that ferroptosis and mitochondrial ROS provide a cohesive mechanistic framework for graft vulnerability at reperfusion. This review emphasizes that while these pathways are critical, clinical translation remains constrained by several factors. Heterogeneity in experimental models and variability in anesthetic regimens complicate the interpretation of results. Furthermore, overreliance on non-specific oxidative stress markers and a lack of validated ferroptosis-related endpoints in human studies limit current understanding.

To advance this field, future research should move beyond general oxidative stress assessments toward biomarker-driven approaches. Integrating ferroptosis-specific markers and mitochondrial function tests with risk stratification of donor livers based on biochemical profiles is essential. 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, emphasizing research-use contexts rather than therapeutic applications.