Integrative approach to alcohol-related liver fibrosis: natural compounds modulating oxidative stress and ferroptosis.

Liver fibrosis, induced by chronic alcohol consumption, is characterized by oxidative stress, inflammation, and the activation of ferroptosis. This study evaluates the hepatoprotective, antioxidant, and antifibrotic effects of natural compounds in mitigating alcohol-induced liver fibrosis. Forty-eight female Albino rats were divided into six groups, including a control, an alcohol-induced fibrosis model, and four treatment groups receiving different combinations of natural products (honeybee products, propolis, curcumin, black seed oil, and wheat germ oil). Biochemical, molecular, histopathological, and in vitro assays (MTT cytotoxicity, wound healing, flow cytometry, and ADME prediction) were conducted to assess liver function, oxidative stress, and ferroptosis markers. The ethanol-induced model exhibited significant hepatic damage, with elevated fibrosis markers (COL1A1, α-SMA, TGF-β), oxidative stress, and ferroptosis activation. Treatment with natural compounds, especially the combination of wheat germ oil and bioactive agents (G3), significantly reduced oxidative stress (p < 0.05), restored Nrf2 and SLC7A11 expression, and improved histopathological outcomes. In vitro assays demonstrated dose-dependent cytotoxicity and optimized dosing for therapeutic applications. G3 treatment normalized cell cycle distribution, reduced hepatic stellate cell activation, and suppressed ferroptosis-associated lipid peroxidation. Natural compounds, particularly the wheat germ oil combination, provide promising hepatoprotective benefits by targeting oxidative stress, ferroptosis, and fibrosis pathways. These findings suggest potential applications for liver disease management, warranting further research into their long-term safety and efficacy. The online version contains supplementary material available at 10.1007/s13205-026-04839-3.