ISG15–CREB1 ISGylation: a stellate cell brake in liver fibrosis

Liver fibrosis remains the critical bottleneck in the progression from chronic liver injury to cirrhosis and hepatocellular carcinoma (HCC). Activated hepatic stellate cells (HSCs) play a central role in this process by secreting excessive extracellular matrix leading to liver scarring, distortion of liver architecture and liver dysfunction.1 Despite intensive efforts to target HSCs and reverse fibrosis, no treatment has yet reached the clinic.

In Gut, Yuan et al identified interferon (IFN)-stimulated gene 15, ISG15, as an intracellular brake of HSC activation and liver fibrosis.2 By uncovering a cell-intrinsic checkpoint that restrains HSC activation, this work highlights a highly selective antifibrotic strategy. Single-cell analyses of liver tissues revealed predominant ISG15 expression in quiescent fibroblast clusters with marked downregulation in activated HSCs and fibrotic mice and human livers, driven by impaired IFN-IRF9 signalling. Strikingly, HSC-specific ISG15 deletion caused spontaneous fibrosis in aged mice and aggravated fibrosis in CCl₄/BDL-induced liver injury. Conversely, ISG15 restoration in HSCs blunted fibrogenesis, reinforcing its role as HSC-intrinsic safeguard. Collectively, these findings establish ISG15 as a non-redundant antifibrotic checkpoint.