FXR acts as a therapeutic target for ulcerative colitis via suppressing ferroptosis

作者：Chenye Zhao, Xiaopeng Li, Mingchao Mu, Li Quan, Hang Yuan, Jianbao Zheng, Wei Zhao, Xuejun Sun, Junhui Yu · 发表于：Molecular Medicine · 年份：2025 · DOI：10.1186/s10020-025-01305-3 · 被引用次数：13 · 研究领域：Ferroptosis and cancer prognosis、Drug Transport and Resistance Mechanisms、Cholesterol and Lipid Metabolism

BACKGROUND: The involvement of ferroptosis in ulcerative colitis (UC) is increasingly acknowledged. Several investigations have revealed the various mechanisms by which the farnesoid X receptor (FXR) inhibits ferroptosis in certain diseases; however, its potential modulation of ferroptosis in UC remains unexplored. METHODS: The characteristics of FXR expression in colitis were evaluated in the GEO database, patient specimens, and mice with DSS-induced colitis. The role of FXR in ferroptosis was investigated by treating colitis mice with the intestine-restricted FXR agonist fexaramine (Fex) intragastrically. In vitro, Caco-2 cells challenged with RSL3 were used to study the role of FXR in modulating ferroptosis in intestinal epithelial cells (IECs). RESULTS: Fex significantly alleviated symptoms and impeded ferroptosis in mice with DSS-induced colitis. In vitro, Fex rescued Caco-2 cells from RSL3-induced ferroptosis. Mechanistically, FXR was capable of binding to the promoter region of SLC7A11 and upregulated the transcription of SLC7A11, which is beneficial for the synthesis of GSH. Knockdown of SLC7A11 partially abrogated the therapeutic effects of Fex, albeit incompletely. Further investigations revealed that FXR can also increase the protein stability of GPX4 by upregulating the deubiquitinase OTUB1. CONCLUSION: This study highlights that FXR exerts therapeutic effects against colitis by antagonizing ferroptosis via transactivation of SLC7A11 and increasing GPX4 stability....