Zhao Chenye, Li Xiaopeng, Mu Mingchao, Quan Liyong, Yuan Hang, Zheng Jianbao, Zhao Wei, Sun Xuejun, Yu Junhui
Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
Department of Orthopedic, Xi'an Chest Hospital, Xi'an, Shaanxi Province, 710100, China.
Mol Med. 2025 Jul 18;31(1):258. doi: 10.1186/s10020-025-01305-3.
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.
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).
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.
This study highlights that FXR exerts therapeutic effects against colitis by antagonizing ferroptosis via transactivation of SLC7A11 and increasing GPX4 stability. These results suggest that FXR may be a therapeutic target for treating colitis by antagonizing ferroptosis.
铁死亡参与溃疡性结肠炎（UC）这一现象日益受到认可。多项研究揭示了法尼酯X受体（FXR）在某些疾病中抑制铁死亡的多种机制；然而，其在UC中对铁死亡的潜在调节作用仍未得到探索。
在基因表达综合数据库（GEO数据库）、患者标本以及葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠中评估FXR在结肠炎中的表达特征。通过给结肠炎小鼠胃内注射肠道特异性FXR激动剂非瑟酮胺（Fex）来研究FXR在铁死亡中的作用。在体外，使用经RSL3处理的人结肠腺癌细胞（Caco - 2细胞）来研究FXR在调节肠上皮细胞（IECs）铁死亡中的作用。
Fex显著减轻了DSS诱导的结肠炎小鼠的症状并抑制了铁死亡。在体外，Fex使Caco - 2细胞免受RSL3诱导的铁死亡。机制上，FXR能够结合溶质载体家族7成员11（SLC7A11）的启动子区域并上调SLC7A11的转录，这有利于谷胱甘肽（GSH）的合成。敲低SLC7A11部分消除了Fex的治疗效果，尽管并不完全。进一步研究表明，FXR还可通过上调去泛素化酶OTUB1来增加谷胱甘肽过氧化物酶4（GPX4）的蛋白质稳定性。
本研究强调FXR通过激活SLC7A11和增加GPX4稳定性来拮抗铁死亡，从而对结肠炎发挥治疗作用。这些结果表明，FXR可能是通过拮抗铁死亡来治疗结肠炎的一个治疗靶点。
