Mechanisms of deoxynivalenol-induced multi-organ toxicity in broiler chickens: The central role of the Rap1/MAPK pathway revealed by network pharmacology and molecular docking.

Abstract

Deoxynivalenol (DON), a prevalent mycotoxin contaminating agricultural commodities worldwide, poses substantial risks to both public health and animal production. While recognized as a primary contaminant in chicken feed, the mechanistic basis of its multi-organ toxicity remains incompletely elucidated. This study employed an integrated approach combining network pharmacology, molecular docking, in silico ADME prediction, and in vivo experiments to systematically investigate the common molecular mechanisms underlying DON-induced damage in broilers, focusing on the liver, spleen, breast muscle, and cecum. Bioinformatic analysis identified 20 core target genes, with KEGG enrichment highlighting the MAPK and Rap1 signalling pathways as central regulatory hubs. In vivo results demonstrated that DON exposure significantly compromised growth performance, evident through reduced body weight and organ coefficients. Histopathological and serological analyses confirmed extensive tissue damage: hepatic injury (elevated AST/ALT, structural lesions), immunotoxicity (increased IgA/IgM, splenic abnormalities), myotoxicity (elevated CK/LDH, muscle degeneration), and intestinal inflammation (upregulated IL-1β/TNF-α, villous atrophy). Critically, DON dysregulated the expression of eight key genes within the MAPK/Rap1 axis, upregulating BRAF, CDC42, CSF1R, IKBKB, PDGFRA, and THBS1 while downregulating IGF1R and MAP2K1, along with increased phosphorylated MAPK protein level. Molecular docking simulations further validated strong binding affinities between DON and these core targets. Complementary ADME prediction further supported the physiological plausibility of these interactions, indicating DON's favorable drug-likeness and potential for intracellular target accessibility. Collectively, this work establishes that DON induces coordinated multi-organ toxicity in broilers primarily through regulation of the Rap1/MAPK signalling network, providing a crucial theoretical foundation for developing targeted interventions against DON exposure in (especially poultry) production, food safety and beyond.