Integrated multi-omics and machine learning approach reveals the mechanism of nicotinamide alleviating PFOS-induced hepatotoxicity

<i>Background</i>: Perfluorooctane sulphonate (PFOS) is a persistent environmental contaminant with well-documented hepatotoxic properties. Nicotinamide, the amide derivative of vitamin B3, is widely utilized as a nutritional supplement and exerts multiple biological benefits. Nonetheless, its potential protective effects against PFOS-induced hepatotoxicity have not yet been reported. <i>Methods</i>: Male mice were administered PFOS (10 mg kg^-1) or vehicle by gavage for 28 days. Transcriptomics, proteomics, machine learning, and network topology algorithms were integrated to identify candidate biomarkers. Up- and down-regulated proteins were queried against the Connectivity Map (CMap) database to predict therapeutic nutrients. <i>In vitro</i>, AML12 cells were pretreated with varying concentrations of nicotinamide and subjected to PFOS-induced injury. The binding of nicotinamide to target proteins was assessed by molecular docking, and its protective effects were validated experimentally. <i>Results</i>: <i>In vivo</i>, PFOS exposure induced marked histological damage, inflammation, and oxidative stress in the mouse liver tissue. Integrated multi-omics analysis identified nucleophosmin (Npm1) as a potential biomarker of PFOS-induced hepatotoxicity. CMap analysis predicted nicotinamide as a candidate therapeutic nutrient. Molecular docking indicated strong binding affinity between nicotinamide and Npm1. <i>In vitro</i>, nicotinamide pretreatment enhanced cell viability and reduced Npm1 protein expression in PFOS-injured AML12 cells. <i>Conclusion</i>: Npm1 may serve as a critical biomarker of PFOS-induced liver injury. Nicotinamide exerts hepatoprotective effects by downregulating Npm1, supporting its potential as a nutritional intervention against PFOS-induced hepatotoxicity.