Multi‐Targeted Hepatoprotection: A Combined Extract of <i>Moringa oleifera</i> and <i>Urtica dioica</i> (MU) Combats Drug‐Induced Oxidative Stress and Inflammation via Antioxidant and Molecular Modulatory Effects

Abstract

This study investigated the hepatoprotective effects of a combined ethanolic extract of Moringa oleifera and methanolic extract of Urtica dioica (MU), F3 (2:1 w/w), against isoniazid (INH) and rifampicin (RIF)-induced liver toxicity in rats. Formulation F3, characterized by high total phenolic (246.45 ± 1.80 µg GAE/mg) and flavonoid (67.07 ± 0.21 µg QE/mg) contents, exhibited potent in vitro antioxidant activity (e.g., DPPH IC50 of 42.66 ± 0.59 µg/mL for F3). Significantly, oral administration of F3 alone (200, 400 mg/kg) did not induce liver toxicity, maintaining normal histopathology similar to controls. Conversely, INH-RIF treatment significantly increased serum liver markers (AST, ALT, ALP, bilirubin, and triglycerides), elevated MDA levels, reduced CAT and GSH activities, and caused severe histopathological damage. The combined extract F3, particularly at 400 mg/kg, significantly reversed these biochemical and histopathological alterations. In silico ADMET, DFT, and docking analyses elucidated multi-targeted mechanisms: DFT predicted high reactivity for compounds such as riboflavin (5a), correlating with antioxidant effects. Docking showed strong binding of oleuropein (3a) and riboflavin (5a) to CYP2E1 and TNF-α, suggesting inhibition of toxic metabolite formation and inflammation. These findings highlight this natural combination's potential as an adjunctive therapy for anti-tuberculosis drug-induced liver injury.