Ferroptosis inhibition enhances liver and lung graft function.

Summary

This translational study identifies early lipid peroxidation as a therapeutic target in human liver transplants and demonstrates that ferroptosis inhibition (FXT-001) preserves graft viability in porcine liver/lung perfusion and split ex vivo perfusion of declined human lungs. Next-generation inhibitors (FXT-002/003) showed improved pharmacokinetics and safety profiles, supporting ferroptosis blockade as a strategy against ischemia-reperfusion injury.

Key Findings

• Early, transient lipid peroxidation increases were identified in human liver transplants, validating a therapeutic target.
• FXT-001 preserved graft viability in ex situ perfusion of porcine liver and lung grafts.
• In split ex vivo perfusion of declined human donor lungs, FXT-001 preserved viability whereas untreated lungs deteriorated.
• Next-generation ferroptosis inhibitors (FXT-002/FXT-003) with improved pharmacokinetics and safety were developed.

Clinical Implications

If validated clinically, ferroptosis inhibitors could be incorporated into ex situ machine perfusion protocols to improve graft quality and expand the donor pool, with potential applications across IRI-associated surgeries.

Limitations

• Preclinical and ex vivo nature limits immediate generalizability to clinical outcomes
• Sample sizes and long-term post-transplant outcomes are not reported
• Regulatory and safety data in humans remain to be established

Future Directions

Conduct first-in-human trials integrating ferroptosis inhibitors into organ machine perfusion, define dosing/exposure-response, and assess graft function and recipient outcomes across transplant types and other IRI contexts.