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

Background

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.

Methods

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. In vitro, 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.

Results

In vivo, 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. In vitro, nicotinamide pretreatment enhanced cell viability and reduced Npm1 protein expression in PFOS-injured AML12 cells.

Conclusion

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.