Characterization of formaldehyde-induced hepatotoxicity based on proteometabolomic analysis

Formaldehyde (FA) is a well-known environmental toxicant used in various industries, including biomedical, agriculture, and textiles, but poses significant health risks. Despite extensive research, the exact hepatotoxic mechanism of FA remains unclear. This study investigated FA-induced liver toxicity through an integrative analysis of proteomics and metabolomics in rat models, identifying 84 differentially expressed proteins and 66 metabolites. Using xMWAS and Reactome software, the study highlighted ferroptosis as a key pathway in FA-induced liver damage. STAT3/HO-1 were identified as crucial protein biomarkers, leading to ferroptosis via lipid peroxide accumulation through iron efflux. Validation through qPCR, western blot, and cell experiments confirmed the involvement of genes like Stat3, Hmox-1, and coagulation-related genes (Fga, Fgb, Fgg, Serpina1, and A2M). This research reveals a novel FA hepatotoxic mechanism involving ferroptosis and complement and coagulation pathways, offering potential for therapeutic interventions.