Mechanistic insights into deoxynivalenol-Induced hepatic cholestasis via IRE1α/HNF1α/FXR signaling dysregulation in mice

文献类型： 外文期刊

第一作者： Wu, Yuting

作者： Wu, Yuting;Lin, Ruqin;Yuan, Qianqian;Sun, Yu;Yuan, Yiwen;Jiang, Tianqing;Jiang, Jun;Mu, Peiqiang;Wen, Jikai;Deng, Yiqun;Wu, Yuting;Deng, Yiqun;Wu, Yuting;Lin, Ruqin;Yuan, Qianqian;Sun, Yu;Yuan, Yiwen;Jiang, Tianqing;Jiang, Jun;Mu, Peiqiang;Wen, Jikai

作者机构：

关键词： Deoxynivalenol (DON); Bile acid (BA); Cholestasis; Endoplasmic reticulum (ER) stress

期刊名称：ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY （ 影响因子：6.1； 五年影响因子：6.4 ）

ISSN： 0147-6513

年卷期： 2025 年 301 卷

页码：

收录情况： SCI

摘要： Deoxynivalenol (DON), a trichothecene mycotoxin ubiquitously contaminating agricultural commodities, foodstuffs, and water systems, poses significant health risks to humans and livestock. As the primary detoxification organ, the liver exhibits marked susceptibility to DON-induced toxicity. Our study demonstrated that DON triggers hepatocellular injury by disrupting bile acid (BA) homeostasis and activating pro-inflammatory cascades. In murine models, DON exposure significantly elevated systemic and intrahepatic total bile acid (TBA) levels while upregulating pro-inflammatory cytokine expression. Notably, the accumulation of conjugated BAs and transcriptional dysregulation of BA-metabolizing genes identified farnesoid X receptor (FXR) suppression as the central mechanism driving DON-mediated cholestasis. Mechanistically, DON activates the Inositol-Requiring Enzyme 1 alpha (IRE1 alpha) branch of the unfolded protein response, leading to hepatic nuclear factor 1 alpha (HNF1 alpha) suppression via RNase-dependent mRNA degradation. This HNF1 alpha downregulation directly attenuates FXR transcription, defining a novel IRE1 alpha-HNF1 alpha-FXR signaling axis in cholestatic pathogenesis. Pharmacological targeting of FXR with GW4064 or inhibition of IRE1 alpha with KIRA6 effectively ameliorated DON-induced cholestasis and hepatocellular damage, validating this axis as a therapeutic target. These findings delineate the molecular crosstalk between endoplasmic reticulum stress and nuclear receptor signaling in mycotoxin hepatotoxicity and establish a mechanistic framework for mitigating DON contamination risks. By elucidating IRE1 alpha's regulatory role and FXR's function in BA homeostasis, this study provides a foundation for developing interventions against foodborne toxicant-induced liver pathologies.

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