Background: Non-alcoholic steatohepatitis (NASH) lacks approved pharmacotherapies despite affecting approximately 25% of the global population. Agrimonia pilosa, a traditional herb with anti-inflammatory and antioxidant properties, remains unexplored for NASH treatment.
Objective: This study investigated the hepatoprotective effects and mechanisms of Agrimonia pilosa extract (APE) in NASH models.
Methods: HepG2 cells were treated with free fatty acids (0.125 mM) and APE (+12.5-50 μg/mL). C57BL/6J mice received a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 12 weeks with APE (25-100 mg/kg/day), silymarin (100 mg/kg/day), or luteolin (20 mg/kg/day). Lipid accumulation, liver enzymes, histopathology, and molecular markers were assessed.
Results: APE dose-dependently reduced lipid accumulation in FFA-treated cells, suppressed lipogenic factors (SREBF1, CEBPA, and PPARG), and upregulated fatty acid oxidation enzymes (CPT1A and PPARA) via AMPK/SIRT1 activation. In NASH mice, APE (100 mg/kg) significantly decreased serum ALT (160.0 ± 49.1 vs. 311.2 ± 66.7 U/L) and AST (96.0 ± 18.7 vs. 219.0 ± 55.7 U/L, p < 0.001), reduced hepatic macrophage infiltration by 68%, and substantially attenuated inflammatory markers (Ccl2, Tnf, and IL6), oxidative stress indicators (NRF2, HMOX1, and CYBB), and fibrogenic markers (ACTA2, COL1A1, and TGFB1) by 83-85% (p < 0.001). Collagen deposition decreased from 5.63 ± 0.39% to 1.54 ± 0.03% (p < 0.001).
Conclusions: APE exerts potent hepatoprotective effects through multi-targeted modulation of lipid metabolism, inflammation, oxidative stress, and fibrosis via AMPK/SIRT1 pathway activation, supporting its potential as a natural therapeutic intervention for NASH.
Keywords: AMPK/SIRT1 signaling pathway; Agrimonia pilosa; inflammation; lipid metabolism; non-alcoholic steatohepatitis; oxidative stress.