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

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 1α (IRE1α) branch of the unfolded protein response, leading to hepatic nuclear factor 1α (HNF1α) suppression via RNase-dependent mRNA degradation. This HNF1α downregulation directly attenuates FXR transcription, defining a novel IRE1α-HNF1α-FXR signaling axis in cholestatic pathogenesis. Pharmacological targeting of FXR with GW4064 or inhibition of IRE1α 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 IRE1α's regulatory role and FXR's function in BA homeostasis, this study provides a foundation for developing interventions against foodborne toxicant-induced liver pathologies.