Protective effects of p-coumaric acid against lead-induced hepatic oxidative stress, inflammation, and apoptosis: Integrated molecular and machine learning-based analysis.

Lead (Pb) exposure is a major environmental health concern that induces hepatic injury through oxidative stress, inflammation, and apoptosis. This study evaluated the hepatoprotective effects of p-coumaric acid (PCA), a phenolic compound, against Pb-induced liver toxicity using integrated molecular and machine-learning approaches. Male rats were allocated into experimental groups and exposed to Pb-acetate (30 mg/kg), while PCA was orally administered at 50 and 100 mg/kg for 14 days. A dataset consisting of 30 adult male rats (n = 6 per group) was analyzed using biochemical, molecular, inflammatory, and histopathological parameters. Oxidative stress markers, antioxidant and apoptotic gene expression, inflammatory protein expression, and liver tissue alterations were assessed. In addition, principal component analysis (PC analysis), correlation heatmap analysis, and Random Forest-based SHAP (Shapley Additive Explanations) analysis were applied to identify key biomarkers associated with Pb toxicity and PCA-mediated protection. Pb exposure caused a pronounced oxidative imbalance, evidenced by significant depletion of antioxidant defenses, including reduced glutathione (GSH) (p < 0.001), glutathione peroxidase (GPx) (p < 0.001), and catalase (Cat) gene expressions (p < 0.001), together with increased malondialdehyde (MDA) levels (p < 0.001). Pb also up-regulated Bax and Casp3 (p < 0.001), down-regulated Bcl-2 (p < 0.01), and activated NF-κB, IL-1β, TNF-α, IL-6, and COX-2 (p < 0.001). Histopathology confirmed severe hepatocellular degeneration and necrosis. PCA treatment attenuated these alterations in a dose-dependent manner, with 100 mg/kg showing the strongest protection (p < 0.05). Overall, PCA alleviates Pb-induced hepatotoxicity by restoring antioxidant defenses, suppressing inflammatory signalling, and inhibiting mitochondrial apoptotic pathways.