Yiqi Huayu Jiedu formula inhibits JAK2/STAT3-mediated partial EMT in treating chronic atrophic gastritis

Abstract

Background: Chronic atrophic gastritis (CAG) is a precursor to gastric cancer, a leading cause of cancer-related deaths worldwide. Despite current therapeutic strategies, preventing the transition from gastritis to cancer remains a challenge. Traditional Chinese Medicine (TCM), particularly the Yiqi-Huayu-Jiedu (YQHYJD) formula, have exhibited promising results in CAG management. However, the pharmacological underpinnings of this formula remain elusive.

Purpose: The study aimed to elucidate the pharmacological mechanisms of the YQHYJD formula in treating CAG and its role in inhibiting the progression to gastric cancer through the modulation of the "inflammation-cancer" sequence.

Methods: Mass spectrometric analysis of YQHYJD formula-containing serum was conducted to determine the active compounds involved in CAG treatment. A CAG rat model was induced using a combination of deoxycholic acid and ammonia, while a gastric precancerous lesion cell model was generated by exposing GES-1 cells to deoxycholic acid. Both models were treated with varying concentrations of the YQHYJD formula to assess its effects of the JAK2/STAT3 signaling-mediated epithelial-mesenchymal transition (EMT) pathway.

Results: Mass spectrometry analysis identified 80 active compounds in the YQHYJD formula, including quercetin. Network pharmacology analysis revealed that these active compounds may exert their therapeutic effects on CAG through various mechanisms, including the JAK/STAT signaling. Using rat and cellular models of CAG, we found that the JAK/STAT pathway is activated alongside partial epithelial-mesenchymal transition (pEMT). YQHYJD treatment effectively mitigated the activation of the JAK2/STAT3 activation and pEMT. Furthermore, the therapeutic effect of the YQHYJD formula was maintained even in the presence of Colivelin or overexpressed STAT3.

Conclusions: The YQHYJD formula treats CAG by inhibiting the JAK2/STAT3 -mediated pEMT, thereby suppressing the gastric "inflammation-cancer" transformation. This study provides mechanistic insights into the efficacy of YQHYJD in CAG treatment and suggests new therapeutic strategies for preventing gastric cancer development.

Keywords: Chinese medicine; Chronic atrophic gastritis; Epithelial-mesenchymal transition (EMT).