Epmedin C Alleviates Deoxynivalenol-Induced Immunotoxicity by Inhibiting Caspase-1 Activation in Chicken Macrophages

Deoxynivalenol (DON), a prevalent mycotoxin in poultry feed, exerts immunotoxicity even at low doses, yet its mechanisms in poultry remain unclear. Here, we evaluated DON's effects using chicken macrophage HD11 cells and one-day-old chicks. <i>In vitro</i>, DON activated the caspase-1/IL-1β pathway, increased reactive oxygen species (ROS), and promoted proinflammatory cytokine release, impairing antibody production. Network pharmacology and molecular docking identified epmedin C, a major flavonoid from Epimedium, as a potential caspase-1 inhibitor. Epmedin C bound strongly to caspase-1, inhibited its activation, reduced ROS, and suppressed cytokine secretion in HD11 cells, while coculture assays confirmed restoration of antibody production. <i>In vivo</i>, dietary epmedin C supplementation alleviated DON-induced immunotoxicity by restoring antibody levels, reducing splenic caspase-1 activity, and preserving immune and intestinal structures. These findings highlight epmedin C as a natural caspase-1 inhibitor that mitigates DON-induced immune damage, offering a promising strategy for mycotoxin detoxification in poultry.