Epigenetic regulation and posttranslational modifications of FXR: underlying mechanisms and implications in digestive diseases.

The incidence of digestive system diseases is increasing, with liver diseases, obesity, inflammatory bowel disease (IBD), and hepatoenteric cancers being prominent contributors to global morbidity and mortality. Targeting farnesoid X receptor (FXR) has emerged as a promising therapeutic strategy for various digestive disorders. FXR is a member of the nuclear receptor superfamily, is expressed primarily in the liver and small intestine, and is activated by bile acids (BAs). Beyond classical ligand-dependent activation, FXR activity is precisely modulated by epigenetic regulation and posttranslational modifications (PTMs), such as DNA methylation, histone methylation and acetylation, noncoding RNA regulation, phosphorylation, acetylation, SUMOylation, ubiquitination, O-glycosylation, methylation, sulfhydration, and poly(ADP-ribosyl)ation. Growing evidence reveals disease-associated alterations in FXR modification patterns, offering novel therapeutic perspectives for digestive pathologies. In this review, we comprehensively summarize the structure of FXR, its regulatory mechanisms through epigenetic modifications and PTMs, and its potential application in the treatment of digestive diseases. The structure of FXR, its regulatory mechanisms through epigenetic modifications and PTMs, and its potential application in the treatment of digestive diseases. Upper: epigenetic regulation of FXR. Below: posttranslational modifications of FXR. OG O-glycosylation, P phosphorylation, SUMO SUMOylation, SSH sulfhydration, Ac acetylation, Me methylation, Ub ubiquitination.