Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis

Liver fibrosis results from chronic liver injury triggered by factors such as viral infection, excess alcohol intake, and lipid accumulation. However, the mechanisms underlying liver fibrosis are not fully understood. Here, we demonstrate that expression of Fibroblast growth factor 18 (Fgf18) is elevated in the livers of mice following induction of chronic liver fibrosis models. Deletion and overexpression of Fgf18 in hepatocytes attenuate and promote liver fibrosis, respectively. Single-cell RNA-sequencing revealed that Lrat+ quiescent hepatic stellate cells (HSCs) are increased in the livers of Fgf18 transgenic mice. Mechanistically, FGF18 stimulates the proliferation of quiescent HSCs by inducing the expression of Ccnd1, resulting in the development of liver fibrosis. Moreover, the expression of FGF18 is correlated with the expression of profibrotic genes, such as COL1A1 and ACTA2, in human liver biopsy samples. Thus, FGF18 promotes liver fibrosis and could serve as a therapeutic target to treat liver fibrosis. Comparisons of global gene expression patterns between control and conditional knockout mice / transgenic mice by bulk RNA-seq (N=3 each).