Deficiency of vitamin D-binding protein exacerbates liver fibrosis by disrupting iron homeostasis via the activation of YAP signaling.

Liver fibrosis is a chronic progressive disease that can advance to cirrhosis or hepatocellular carcinoma if untreated. While liver transplantation remains the only curative option for end-stage fibrosis, the development of alternative therapies is urgently needed. In this study, we investigated the role of vitamin D-binding protein (VDBP) in hepatic fibrosis using clinical samples and a CCl4-induced mouse model. We observed significant downregulation of VDBP in fibrotic human and murine livers, suggesting that VDBP may serve as a potential biomarker for disease progression. VDBP knockout (VDBP-KO) mice exhibited exacerbated fibrosis, iron overload, and ferroptosis activation, accompanied by dysregulation of the Hippo-YAP pathway. In vitro, VDBP overexpression reversed these effects, while in vivo treatment with the YAP inhibitor verteporfin attenuated fibrosis, normalized iron homeostasis, and suppressed ferroptosis in VDBP-KO mice. Our findings demonstrate that VDBP plays a pivotal role in maintaining iron balance, inhibiting YAP signaling, and preventing ferroptosis during fibrogenesis. Elucidating the molecular mechanisms of VDBP and its downstream pathways may provide novel therapeutic targets for liver fibrosis. This could significantly improve the clinical management of hepatic fibrosis and offer new hope for patients suffering from this debilitating disease.