Repression of the ERRγ-CYP2E1 pathway by FGF4 mitigates alcohol-associated liver injury

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) represents a critical global health challenge characterized by liver damage resulting from excessive alcohol consumption. Early detection and timely intervention are essential for optimizing patient outcomes. However, the mechanisms underlying alcohol-induced liver injury have not been fully elucidated. Fibroblast growth factor 4 (FGF4) has been implicated in the progression of various liver diseases. This study aims to elucidate the role of FGF4 in the pathogenesis of ALD. APPROACH AND RESULTS: We analyzed human liver specimens and observed significant upregulation of FGF4 mRNA and protein levels in patients with ALD. Consistent findings were noted in mouse models subjected to a Lieber-DeCarli liquid diet. Importantly, hepatic FGF4 expression exhibited a positive correlation with ALD severity in both human subjects and murine models. Hepatocyte-specific deletion of Fgf4 ( Fgf4 -LKO) exacerbated alcohol-induced liver injury through increased oxidative stress, inflammation, and apoptosis. Specifically, Fgf4 -LKO mice demonstrated heightened susceptibility to ethanol plus CCl 4 -induced fibrosis and liver injury. However, treatment with the ERRγ inverse agonist GSK5182 and CYP2E1 inhibitor chlormethiazole (CMZ) mitigated the exacerbated liver injury associated with Fgf4 deficiency. Mechanistic investigations revealed that FGFR4 phosphorylates ERRγ, promoting its ubiquitination and degradation in hepatocytes. Hepatic-specific knockout of Fgfr4 intensified alcohol-induced liver injury and nullified the protective conferred of recombinant FGF4 △NT . CONCLUSIONS: Our study identifies FGF4 as a stress-responsive regulator in liver pathophysiology, operating through an FGFR4-mediated ERRγ-CYP2E1 signaling pathway. These results underscore the potential of FGF4 and its downstream pathways as therapeutic targets for ALD treatment.