Yi Shan,1,2 Yang Ma,1,2 Hanfei Chen,1,2 Sichao Zhao,1,2 Mingzhu Shi,1,2 Min Bai,1,2 Junrui Hu1,2 

1College of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, 750004, People’s Republic of China; 2Key Laboratory of Ningxia Ethnomedicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, 750004, People’s Republic of China

Correspondence: Junrui Hu, Email 89463882@qq.com Min Bai, Email 1115487589@qq.com

Purpose: Precancerous lesions of gastric cancer (PLGC) represent a crucial juncture in the transformation from gastritis to gastric cancer. Qijie Xiaopi Decoction (QJXPD), a Chinese herbal medicine formulation that has been applied in clinical practice to manage PLGC, which is capable of effectively relieving the symptoms experienced by patients such conditions. However, its mechanism of action remains unclear. The aim of this study is to elucidate the mechanism of action of QJXPD in the treatment of PLGC.
Methods: Ultra-high-performance liquid chromatography coupled with hybrid quadrupole-orbitrap tandem mass spectrometry (UHPLC-Q-Exactive Orbitrap-MS) was employed to pinpoint the chemical components of QJXPD. On this basis, network pharmacology and molecular docking were employed to pinpoint the main ingredients, probable targets, and associated pathways of QJXPD in treating of PLGC. A PLGC rat model was replicated using a compound modeling method mainly based on N-methyl-N’-nitro-N-nitrosoguanidine (MNNG), to observe the therapeutic effects of QJXPD on PLGC.
Results: The undiluted QJXPD solution contained 1069 compounds. Network pharmacology analysis revealed that QJXPD’s anti-PLGC effects involved 119 active ingredients and 332 potential targets, primarily enriched in the PI3K/AKT pathway. Protein-protein interaction (PPI) analysis suggested that TP53, AKT1, SRC, STAT3, and EGFR were the key targets. Through molecular docking, it was discovered that the core targets exhibited a strong binding affinity with the primary active ingredients. Animal experiments have verified that QJXPD can significantly improve the general condition in PLGC rats, increase body weight, repair the damaged gastric mucosa and diminish the inflammatory infiltration, induce apoptosis of gastric mucosal cells, upregulate the expression of LC3, Beclin-1, and Bax and downregulate the expression of p62 and Bcl-2. The PI3K/AKT/mTOR pathway was inhibited by QJXPD.
Conclusion: QJXPD effectively alleviated the pathological injury of gastric mucosa in PLGC rats by inhibiting the PI3K/AKT/mTOR signaling pathway and inducing cellular autophagy and apoptosis.

Keywords: Qijie Xiaopi decoction, precancerous lesions of gastric cancer, network pharmacology, PI3K/AKT /mTOR, autophagy, apoptosis