Epigenetic Regulation of Manganese‐Induced Hepatotoxicity Uncovering Histone Demethylation‐Associated Gene Networks

Excessive manganese (Mn) exposure can result in significant liver toxicity in humans and animals. Histone demethylation, a crucial epigenetic modification, is believed to play a pivotal role in liver disease progression. However, the involvement of histone demethylation-associated genes in Mn-induced hepatotoxicity remains poorly understood. This study aimed to identify these genes related to Mn exposure. We analyzed gene expression data, which included liver samples treated with manganese chloride (MnCl₂₎ and control samples. Our analysis revealed 351 differentially expressed genes (DEGs) on Day 3 and 494 DEGs on Day 5 in livers treated with 700 mg/kg MnCl₂. Notably, we identified 24 overlapping histone demethylation-associated DEGs across both time points. Biological process analysis indicated that these DEGs are linked to organ regeneration, cell proliferation, responses to xenobiotic substances and toxins, bile transport, fatty acid metabolism, and posttranscriptional regulation. Pathway analysis identified associations with IL-17 signaling, cAMP pathways, chemical carcinogenesis, and parathyroid hormone synthesis and action. Furthermore, we highlighted several histone demethylation-associated hub genes, including CDKN1A, PPARA, CYP7A1, CAV1, GDF15, and GRP, implicated in Mn-induced hepatotoxicity.