Medium‐Chain Fatty Acids Ameliorate Liver Fibrosis by Phosphorylating Hepatic Stellate Cell Forkhead Box Protein O1

ABSTRACT Background and Aims Liver fibrosis is a common adverse prognostic factor in various liver conditions. Medium‐chain fatty acids (MCFAs), unique fatty acids transported directly to the liver, undergo rapid metabolism, providing energy to hepatocytes and acting as signalling molecules that mediate diverse cellular functions. Nonetheless, the precise impact of MCFAs on the pathogenesis of liver fibrosis remains incompletely understood. This study aimed to investigate the anti‐fibrotic role of MCFAs and their therapeutic potential for liver fibrosis. Methods To investigate the effects of MCFAs on liver fibrosis and pathophysiology, we conducted experiments utilising a male mouse model of metabolic dysfunction‐associated steatohepatitis (MASH). The anti‐fibrotic effect of MCFAs was evaluated using human hepatic stellate cells (hHSCs). We analysed the role of forkhead box protein O1 (FOXO1), a transcription factor closely involved in metabolic regulation, in MCFA‐stimulated HSCs. Results MCFA feeding significantly improved liver fibrosis and lipid accumulation in mice. Additionally, C10 inhibited collagen production, migration, and proliferation of activated hHSCs. FOXO1 inhibitors suppressed collagen production by hHSCs, and C10 stimulation induced FOXO1 Ser256 phosphorylation. Mechanistically, C10 induced phosphorylation of FOXO1 via AKT phosphorylation in a PI3K‐independent manner. Notably, elevated levels of phosphorylated FOXO1 were observed in hepatic tissue from MASH model mice treated with an MCFA‐rich diet, accompanied by its translocation from the nucleus to the cytoplasm. Conclusions MCFAs, particularly C10, may modulate hHSC transcriptional inactivation through phosphorylation of the Akt–FOXO1 pathway. This mechanism of regulating the hHSC function via C10 might represent a novel therapeutic approach for liver fibrosis.