Lin28A Drives hepatic fibrosis by suppressing HMGA2/HIF-1α-Dependent ferroptosis in hepatic stellate cells

Effective therapies for liver fibrosis are lacking. The RNA-binding protein Lin28A is upregulated in human cirrhotic and mouse fibrotic livers, where it localizes to activated hepatic stellate cells (HSCs). HSCs-specific overexpression of Lin28A worsened carbon tetrachloride (CCl₄)-induced fibrosis in mice. In LX-2 and primary mouse HSCs, Lin28A knockdown suppressed activation and induced hallmarks of ferroptosis, including mitochondrial damage, lipid peroxidation, and glutathione depletion. Mechanistically, Lin28A repressed the maturation of let-7 microRNAs, leading to increased expression of its target, high-mobility group AT-hook 2 (HMGA2). HMGA2, alongside hypoxia-inducible factor-1α (HIF-1α), contributed to the downregulation of the ferroptosis defense proteins SLC7A11 and GPX4. Notably, the anti-fibrotic effects of the Lin28A inhibitor C1632 were dependent on ferroptosis induction, as co-treatment with ferrostatin-1 reversed its impact on HSCS activation and death. In vivo, C1632 treatment alleviated CCl₄-induced liver fibrosis. These results identify Lin28A as a regulator of HSCS ferroptosis and a potential target for anti-fibrotic therapy.