Epiberberine alleviates cadmium-induced duodenal inflammation in Hu sheep by inhibiting HIF-1 signaling pathway

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Environmental cadmium (Cd) exposure not only poses a significant threat to livestock health but also induces intestinal disorders in sheep. As a critical region for digestion and absorption, damage to the duodenum directly impairs systemic health. To elucidate the key mechanisms underlying Cd-induced duodenal injury and identify preventive and therapeutic strategies, this study utilized Cd-exposed Hu sheep as experimental models and applied multi-omics technologies, including non-targeted metabolomics, proteomics, and transcriptomics. The results showed that Cd exposure caused severe damage to the duodenum of Hu sheep, characterized by inflammatory cell infiltration and disruption of the intestinal barrier. Multi-omics analysis revealed that Cd exposure reduced levels of beneficial metabolites (such as vitamin K and riboflavin) while activating the HIF-1 signaling pathway. Through network pharmacology screening and molecular docking validation, epiberberine (EPI) was identified as a promising therapeutic candidate targeting the HIF-1α. Mouse fecal microbiota transplantation (FMT) experiments further confirmed that EPI can restore the intestinal barrier integrity, mitigate inflammatory responses, and effectively alleviate Cd-induced duodenal damage by inhibiting the HIF-1 signaling pathway, providing a novel approach for preventing and treating intestinal diseases under cadmium exposure. • We successfully modeled the hazards of cadmium exposure to Hu sheep, which were obvious and serious. • Cadmium exposure reduced the levels of metabolites: Lysophosphatidic acid, Vitamin K, Riboflavin, Daidzein and Pantothenic acid. • HIF1 signaling pathway was activated after cadmium exposure. • Epiberberine effectively alleviated cadmium-induced duodenal injury by inhibiting the HIF-1 signaling pathway.

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