Integrative network toxicology and mendelian randomization reveal mechanisms of malachite green carcinogenicity and hepatorenal toxicity

Malachite green (MG), a persistent aquaculture antimicrobial agent, poses potential carcinogenic and hepatorenal toxicity risks through dietary exposure, yet its molecular mechanisms remain incompletely characterized. This study integrated network toxicology, molecular docking and Mendelian randomization to explore MG-induced carcinogenicity and hepato-nephrotoxicity. It predicted MG targets and retrieved disease genes via multiple databases, followed by PPI, GO, KEGG, survival analysis and MR analyses. Potential MG targets were predicted using multiple databases, intersected with genes associated with carcinogenicity, liver injury, and kidney injury, identifying 99, 61, and 52 common targets, respectively. Protein–protein interaction (PPI) network analysis identified TP53, EGFR, BCL2, ESR1, NFKB1, MAPK3, and MAPK1 as core hub genes. Functional enrichment revealed involvement in oxidative stress response, cellular senescence, apoptosis, and p53 signaling pathways. Survival analysis indicated significant associations between several of these genes and survival outcomes in Kidney renal clear cell carcinoma (KIRC). Molecular docking demonstrated that MG binds to these core genes via interactions including hydrogen bonds, hydrophobic interactions, etc., with binding energies ranging from −6.4 to −10.8 kcal/mol. Critically, MR analysis identified MAPK1 and MAPK3 as significant causal risk factors for hepatocellular carcinoma (HCC), providing genetic epidemiological evidence linking MG exposure to cancer development. These findings suggest MG exerts carcinogenic and hepatorenal toxicity through multi-target mechanisms, with MAPK signaling as a key pathway. This integrative computational approach provides mechanistic insights into MG's health risks and supports safety reassessment in aquaculture practices, though experimental validation is warranted.