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

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

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.

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Fig. 1: Schematic diagram of four FXRα protein isoforms.
Fig. 2: Acetylation of FXR under physiological and pathological conditions.
Fig. 3: SUMO-ubiquitin activation-degradation pathway under pathological conditions.
Fig. 4: O-glycosylation of FXR.
Fig. 5: Enzymes that mediate the interplay between epigenetic modifications and posttranslational modifications (PTMs) of FXR.
Fig. 6: Variation in epigenetic modifications of FXR in colon cancer.
Fig. 7: Variation in epigenetic modifications and PTMs of FXR in liver diseases.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (82404775, 82301823 and 82373928); Fundamental Research Funds for the Central Universities (Project for Young Teachers) (2042023kf0064); Zhongnan Hospital of Wuhan University Science, Technology and Innovation Seed Fund (CXPY2024025); National Key R&D Program of China (No. 2024YFC2815900); Fundamental Research Funds for the Central Universities (No. 2042025kf0062); Research Fund from Medical Sci-Tech Innovation Platform of Zhongnan Hospital, Wuhan University (PTXM2025015); Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University (ZNLH202319); and Undergraduate Training Programs for Innovation and Entrepreneurship of Wuhan University (S202510486461&W202510486456).

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Authors and Affiliations

  1. Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, 430071, China

    Qian-rui Mi, Cai-qian Wu, Cheng-guo Lv, Ke-er Zhao, Zhao-feng Liu, Peng-fei Xu & Ling Li

  2. School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China

    Peng-fei Xu

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  1. Qian-rui Mi
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  2. Cai-qian Wu
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  5. Zhao-feng Liu
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  6. Peng-fei Xu
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  7. Ling Li
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Contributions

QRM conducted the literature review and wrote the draft of the manuscript. CQW assisted in the literature search. CGL, KEZ, and ZFL provided useful comments and suggestions. PFX and LL revised the manuscript. All the authors have agreed both to be personally accountable for their own contributions and to ensure that questions related to the accuracy or integrity of any part of the work are addressed. All the authors have read and approved the final manuscript.

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Correspondence to Peng-fei Xu or Ling Li.

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Mi, Qr., Wu, Cq., Lv, Cg. et al. Epigenetic regulation and posttranslational modifications of FXR: underlying mechanisms and implications in digestive diseases. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-025-01726-0

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