Lead-induced Hepatotoxicity in Rat Hepatocytes: a Transcriptomic Network Analysis Reveals Key Molecular Insights

Lead (Pb), a ubiquitous environmental pollutant, poses significant hepatotoxic risks in mammalian systems. Despite its widespread exposure, the precise molecular mechanisms driving Pb-induced liver injury remain incompletely understood. This investigation employed a systems biology approach to delineate critical molecular networks and hub genes mediating Pb hepatotoxicity through integrative analysis of GEO hepatotoxicity datasets. Transcriptomic profiling of rat primary hepatocytes (RPHCs) exposed to 10 ppm Pb(NO3)₂ versus controls identified 1,047 differentially expressed genes (DEGs), with prominent enrichment in: (1) oxidative stress response; (2) hepatic development; (3) lipid metabolism; and (4) xenobiotic response pathways. Multidimensional pathway analysis demonstrated significant involvement of nine core signaling cascades: metabolic pathways, PPAR signaling, MAPK cascade, PI3K-Akt axis, TNF pathway, mineral absorption, hepatitis B infection, fatty acid catabolism, cell cycle regulation, and IL-17 signaling. Through protein-protein interaction network analysis, we systematically identified 22 molecular hubs (11 upregulated: FASN, CYP2E1, ALDH1A1, CYP3A2, HMGCR, UGT2B1, CYP2B3, UGT2A1, SORD, SQLE, and CYP3A62; 11 downregulated: CCNA2, CDK1, CCNB1, PLK1, AURKA, TOP2A, KIF11, BUB1B, NUF2, AURKB, and EXO1) that functionally coalesce in five critical pathways: (i) core metabolic processes; (ii) bile secretion; (iii) chemical carcinogenesis; (iv) steroid hormone biosynthesis; and (v) cytochrome P450-mediated xenobiotic metabolism. This study establishes a comprehensive molecular framework for Pb hepatotoxicity, revealing novel mechanistic insights and potential therapeutic targets for heavy metal-induced liver injury. The identified hub genes and pathways provide a valuable resource for future toxicological investigations and intervention strategies.