Pumpkin seed oil improves hepatotoxicity in rats through inhibition of CYP2E1 and activation of Nrf2 signaling pathways.

Pumpkin seed oil (PSO) possesses multiple pharmacological properties, including antioxidant, anti-inflammatory, and anti-apoptotic effects. Given that paracetamol (PCM) is a common cause of drug-induced hepatic injury, the present study aimed to evaluate the hepatoprotective potential of PSO against PCM-induced liver toxicity in rats and to elucidate its underlying mechanisms. Male albino rats were allocated into six groups (n = 6): control, PCM, silymarin (SLM, 50 mg/kg/day), PSO (1.5 mg/kg/day), SLM + PCM, and PSO + PCM. Serum and liver samples were examined for biochemical, molecular, and histopathological changes. GC-MS analysis identified six major fatty acid methyl esters in PSO, which may contribute to its biological activity. PSO significantly mitigated PCM-induced hepatotoxicity by restoring liver function markers, enhancing antioxidant defenses via downregulation of CYP2E1 and activation of Nrf2, and attenuating inflammation through suppression of TNF-α and IL-1β while elevating IL-10 levels. Moreover, PSO reduced TGF-β expression and improved hepatic regeneration. Histopathological evaluation confirmed the protective effects, and modulation of BAX/Bcl-2 balance indicated its anti-apoptotic action. In conclusion, PSO exerts potent hepatoprotective effects against PCM-induced liver injury, likely mediated by its bioactive constituents through modulation of CYP2E1 and Nrf2 signaling pathways. These findings highlight PSO as a promising natural candidate for further preclinical and clinical evaluation in hepatoprotection.