Ferroptosis inhibition enhances liver and lung graft function.

Summary

This translational study identifies early lipid peroxidation during human liver transplantation and demonstrates that ferroptosis inhibitors (FXT-001) preserve porcine liver and lung grafts and sustain viability of declined human lungs during split ex vivo perfusion. Second-generation compounds (FXT-002/003) improved PK and safety, positioning ferroptosis blockade as a druggable axis for ischemia–reperfusion injury in transplantation.

Key Findings

• Early, transient lipid peroxidation was detected in human liver transplants and validated as a target.
• FXT-001 protected porcine liver and lung grafts during ex situ perfusion.
• In split ex vivo perfusion of declined human lungs, FXT-001 preserved graft viability whereas controls deteriorated.
• Next-generation inhibitors (FXT-002/FXT-003) with improved PK/safety were developed.

Clinical Implications

Ferroptosis inhibitors could be incorporated into ex vivo lung perfusion and liver perfusion protocols to reduce ischemia–reperfusion injury, potentially improving utilization and early function of marginal grafts. Early-phase clinical trials in EVLP/EVLP-like platforms are warranted.

Limitations

• Preclinical study without randomized clinical outcomes
• Sample sizes for declined human lung split-perfusion experiments are not reported and likely small

Future Directions

Conduct phase 1/2 trials integrating ferroptosis inhibitors into EVLP/ELVP protocols, define dose-exposure-response in human grafts, and assess early post-transplant outcomes including PGD and ICU metrics.