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. 2025 Oct:238:152-168.
doi: 10.1016/j.freeradbiomed.2025.06.039. Epub 2025 Jun 22.

FXR overexpression alleviates cholestasis via NLRC4 inflammasome suppression and bile acid homeostasis regulation

Wenyu Wang  1 , Lin Li  1 , Xia Li  1 , Jiaqi Chen  1 , Rui Wang  1 , Qi Yang  1 , Yifan Qu  1 , Changyuan Wang  1 , Ting Fu  2 , Qiang Meng  3
Affiliations

FXR overexpression alleviates cholestasis via NLRC4 inflammasome suppression and bile acid homeostasis regulation

Wenyu Wang et al. Free Radic Biol Med. 2025 Oct.

Abstract

Cholestasis, a major driver of liver disease progression, is characterized by toxic bile acid accumulation due to impaired bile flow, potentially leading to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. To date, the pathogenesis of cholestasis has remained incompletely understood. In the present study, we investigated the role of farnesoid X receptor (FXR) in modulating the NLR family CARD domain-containing protein 4 (NLRC4) inflammasome activity using in vitro (AML-12 hepatocytes) and in vivo (C57BL/6 mice) models of lithocholic acid (LCA)-induced cholestasis. LCA suppressed FXR expression, downregulated bile acid transporters (Bsep, Mrp2, Ntcp), and elevated serum biomarkers of liver injury. Through restored hepatic function by FXR lentiviral vectors, FXR overexpression reduced bile acid accumulation and mitigated inflammation and oxidative stress. In addition, FXR overexpression suppressed bile acid synthesis enzymes (Cyp7a1, Cyp8b1) by upregulating Shp and Fgf15, while enhancing detoxification through Ugt1a1 and Sult2a1. Interestingly, molecular docking analysis and Co-IP experiments demonstrated a direct interaction between FXR and NLRC4. Furthermore, FXR overexpression significantly inhibited NLRC4 inflammasome activation and decreased the expression of NLRC4, caspase-1, IL-1β, and IL-18, thereby attenuating inflammation and oxidative stress. Conversely, FXR knockdown reversed these effects. In addition, to delineate the contribution of NLRC4 inflammasome activation to IL-18 and IL-1β elevation, NLRC4-targeting siRNA-mediated knockdown and NLRC4-encoding plasmid-driven overexpression strategies were systematically employed. Furthermore, DCFH-DA staining was adopted to visualize reactive oxygen species (ROS). In conclusion, for the first time, we found that FXR overexpression alleviates LCA-induced cholestasis by regulating bile acid metabolism and inhibiting NLRC4 inflammasome activation, providing a novel therapeutic strategy for drug development targeting the FXR-NLRC4 axis.

Keywords: Bile acid metabolism; Cholestasis; Farnesoid X receptor (FXR); NLRC4 inflammasome; Oxidative stress.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.We further confirm that any aspect of the work covered in this manuscript that has involved experimental animals has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. All animal experiments were conducted in accordance with the UK Animals (Scientific Procedures) Act 1986 and associated guidelines, the Directive 2010/63/EU ff the European Parliament and of the council on the protection of animals used for scientific purposes or the NIH guide for the care and use of laboratory animals (NIH Publication No. 80-23; revised 1978).We understand that the Corresponding Author is the sole contact for the Editorial process. She is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author and which has been configured to accept email.

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