BACKGROUND AND AIMS

Liver fibrosis, a progressive condition driven by chronic liver injury and excessive scar tissue formation, can lead to cirrhosis, a life-threatening disease. Activation of hepatic stellate cells (HSCs) is central to fibrosis progression, yet current therapies fail to halt or reverse this process. This study evaluated a combination therapy targeting HSCs to ameliorate fibrosis and promote liver repair.

METHODS

A small molecule cocktail, SBCH (SB431542, a TGF-β inhibitor, and CHIR99021, a GSK-3 inhibitor), was tested in three fibrosis models: CCl-induced, bile duct ligation (BDL) and non-alcoholic steatohepatitis (NASH) with diethylnitrosamine (DEN). Therapeutic effects were assessed using phenotypic analyses, in vivo tracing and single-cell RNA sequencing to uncover mechanisms.

RESULTS

SBCH significantly reduced fibrosis in all models by inhibiting HSC activation and fibrogenic activity. The suppression of PI3K/Akt pathway and EMT cascade contribute to the fibrosis-ameliorating effect of SBCH treatment. Furthermore, in vivo tracing and single-cell RNA sequencing revealed that SBCH induced the conversion of activated HSCs into hepatocyte-like cells (ciHeps), which integrated into liver tissue, repaired liver damage and restored liver integrity and function.

CONCLUSIONS

SBCH mitigates liver fibrosis through multifaceted mechanisms, including the inhibition of HSC activation, suppression of fibrogenic activity and regulation of key signalling pathways such as PI3K/Akt and EMT. In addition, SBCH induces the trans-differentiation of activated HSCs into hepatocyte-like cells (ciHeps), effectively reducing pathogenic HSCs while increasing functional ciHeps. This dual-target approach not only facilitates liver tissue repair but also restores liver function, offering a promising therapeutic strategy for liver fibrosis and cirrhosis, with potential applications in conditions arising from various aetiologies of liver injury.