Integrated Network Toxicology and Transcriptomics Reveal Molecular Mechanisms of Cadmium-Exposed Liver Injury in...

Cadmium (Cd) is an environmental toxicant that poses significant risks to food safety and public health through its bioaccumulation in the food chain. The liver is a primary target for chronic Cd toxicity, yet the system-level mechanisms, particularly in physiologically relevant swine models, remain incompletely understood. This study employed an integrated multi-omics approach to elucidate the mechanisms of Cd-exposed hepatotoxicity in weaned piglets. We combined histopathological examination, transmission electron microscopy, and transcriptome sequencing. Our results revealed severe hepatic damage, characterized by disorganized architecture, vacuolar degeneration, mitochondrial dysfunction, and autophagic activation. Network toxicology predicted 3727 potential targets of Cd-exposed liver injury, while transcriptomics identified 1092 differentially expressed genes (DEGs). Crucially, the convergent analysis of both datasets demonstrated that the PI3K-Akt signaling pathway was the central hub, pinpointing it as a pivotal mechanism in Cd-driven hepatotoxicity. Functional enrichment analyses further highlighted dysregulation in immune-inflammatory responses, lipid metabolism, and oxidative stress. Our findings provide a comprehensive systems-level perspective on chronic Cd hepatotoxicity in a translational swine model. We propose the PI3K-Akt pathway and other identified core targets (EGFR, histones, ribosomal proteins) as critical biomarkers for monitoring Cd contamination in swine production chains, offering valuable insights for environmental risk assessment and agricultural product safety.