Heshuxiaoji pill suppresses steatohepatitis and fibrosis by regulating the AngII-BACH1 mediated vasoconstriction

Abstract

Ethnopharmacological relevance

Non-alcoholic steatohepatitis (NASH), a widespread hepatic affliction marked by hepatic fibrosis progression towards hepatocellular carcinoma, is significantly influenced by endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT). Although Heshuxiaoji (HSXJ) Pill, an empirical prescription formulated by Prof. Tongjiao Sun has demonstrated significant efficacy in mitigating steatohepatitis and fibrosis, the precise mechanisms underlying its therapeutic effects remain to be fully elucidated.

Aim of the study

To investigate the antifibrotic effect of HSXJ pill and to explore its mechanism in vivo and in vitro.

Materials and methods

To probe the antifibrotic impact of HSXJ pill and unravel its mechanisms, murine liver fibrosis and NASH models were induced in vivo via Western diet and CCl₄ injection. In vitro, human umbilical vein endothelial cells were stimulated with AngII, followed by Western blot analysis. Additionally, liver biopsies from patients with mild-to-moderate fibrosis (S1–S2) were utilized to verify EndMT involvement in fibrosis.

Results

In the hepatocyte sections exhibiting human liver fibrosis, we observed a significant upregulation of AngII and the transcription factor BTB and CNC homology 1 (BACH1). Genetic ablation of AngII significantly ameliorates hepatic fibrosis and EndMT, while attenuating pathological angiogenesis via decreased BACH1 expression. In contrast, AngII overexpression exacerbates these conditions. In vivo, the HSXJ pill effectively alleviates hepatic fibrosis, reduces alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and suppresses BACH1 and AngII production, thereby inhibiting EndMT. In vitro, the pill mitigates EndMT-associated fibrosis by regulating BACH1 to inhibit AngII activation.

Conclusion

The study indicates that the HSXJ pill effectively diminishes hepatocyte injury markers and alleviates liver fibrosis, with optimal efficacy at medium/high doses. BACH1 serves as a key regulator of hepatic fibrosis via modulation of AngII expression.