Mechanism of Huangqishihu Decoction in Treating Liver Fibrosis in Rats Model via Regulation of Oxidative Stress and Nrf2 Signaling Pathway.

INTRODUCTION

Liver fibrosis (LF), a pathological wound-healing response to chronic injury, lacks effective pharmacological treatments. While Huangqishihu Decoction (HQSHD) shows clinical efficacy against LF, its molecular mechanisms remain unclear. This study investigated HQSHD's anti-fibrotic mechanisms through integrated network pharmacology and experimental validation.

METHODS

Active compounds and targets were identified using TCMSP, Batman-TCM, and GeneCards databases. Protein-protein interaction networks were constructed using STRING, and pathway analysis was performed in Metascape. Molecular docking validated compound-target interactions. In vivo validation was performed in CCl4-induced fibrotic rats, assessing serum biochemistry, histopathology, and molecular markers (qRT-PCR/Western blot).

RESULTS

We identified 64 bioactive compounds in HQSHD and 154 LF-related targets. Core targets (AKT1, CASP3, BCL2, STAT3) modulated multiple pathways including Nrf2 signaling. Molecular docking confirmed strong binding (energy < -7.0 kcal/mol) between the key compounds (quercetin and luteolin) and their targets. In vivo, HQSHD significantly reduced ALT (p<0.01), hydroxyproline (p<0.01), α-SMA (p<0.05), and collagen I (p<0.05) while upregulating Nrf2/HO-1 (p<0.05). It restored apoptosis balance (CASP3↑/BCL2↓, p<0.05).

DISCUSSION: HQSHD exerts anti-fibrotic effects through: 1) ECM (extracellular matrix) reduction via α-SMA/collagen I suppression, 2) Nrf2-mediated antioxidant activation, and 3) apoptosis regulation. This multi-target action addresses key LF drivers, including oxidative stress and inflammation.

CONCLUSION

HQSHD combats LF via coordinated modulation of ECM deposition, oxidative stress, and apoptosis. Our findings provide mechanistic validation for its clinical use and highlight its potential as a multi-target anti-fibrotic therapy.