A pig model of human radiation-induced veno-occlusive liver disease reveals ferroptosis as a therapeutic target.

Radiation-induced liver disease (RILD) poses a major clinical challenge in radiotherapy, transplantation preconditioning, or radiation accidents, yet its pathogenesis is poorly understood due to limited animal models. Here, we establish a translational pig model recapitulating human RILD pathology within 4 weeks post-40 Gy irradiation, featuring veno-occlusive disease (VOD) and centrilobular necrosis. Single-cell atlas analyses identify ferroptosis as a key driver of hepatocyte death during RILD initiation. Ferroptosis inhibition with liproxstatin-1 (Lip-1) not only prevents RILD progression but also reverses histological damage and restores liver function. Mechanistically, Lip-1 treatment restores dysregulated gene expression profiles, particularly associated with hepatocyte ferroptosis, while stimulating hepatic regeneration via coordinated proliferation of hepatocytes and endothelial cells. Our findings establish ferroptosis inhibition as a therapeutic strategy for RILD, demonstrating its dual role in cytoprotection and regeneration. This large animal model provides a robust platform to optimize radiotherapy regimens, improve transplant conditioning, and develop targeted radioprotectants.