Lan Liang,1,2,* Chenming He,3,* Xue Han,4,* Jia Liu,5 Liuhong Yang,5 Fengjiao Chang,6 Yami Zhang,7 Jie Lin5,8 

1The First Clinical Medical School, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of China; 2College of Nursing, Shaanxi Energy Institute, Xianyang, People’s Republic of China; 3LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Xijing 986 Hospital Department, Air Force Medical University, Xian, People’s Republic of China; 5School of Basic Medical Sciences, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of China; 6School of Nursing, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of China; 7The Fifth Oncology Department, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of China; 8Shaanxi Provincial Key Laboratory of TCM Constitution and Disease Prevention, Xianyang, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jie Lin; Yami Zhang, Email linjie0921@sohu.com; zhangyamiysh@163.com

Background: Precancerous lesions of gastric cancer (PLGC) represent critical stages in gastric cancer progression, with a high risk of malignancy. Current treatments, such as Helicobacter pylori eradication, show limited efficacy in reversing precancerous molecular changes. Zuojin Pill (ZJP), a traditional Chinese medicine, has demonstrated potential for treating digestive disorders and may offer a promising approach for PLGC intervention.
Objective: This study aims to investigate the therapeutic effects and mechanisms of ZJP in treating PLGC, focusing on its active components, target pathways, and molecular interactions. By using advanced analytical techniques, we provide a scientific foundation for ZJP’s potential application in early gastric cancer intervention.
Methods: Using ultra-high performance liquid chromatography-quadrupole orbitrap high-resolution mass spectrometry (UPLC-Q-Orbitrap HRMS), we identified active components in ZJP. A network pharmacology approach was then applied to construct a “ZJP-compound-target-disease” network. Molecular docking and molecular dynamics simulations were conducted to analyze the stability and interactions of the main active components of ZJP with core protein targets in PLGC. Animal experiments were used to validate significant targets and pathways in vivo.
Results: Tangeritin, Isorhamnetin, Caffeic Acid, Azelaic Acid, and Adenosine were identified as the main active components of ZJP in the treatment of PLGC, with key targets including PIK3R1, MAPK3, SRC, JAK2, STAT3, and PIK3CA. Molecular docking and molecular dynamics simulations further confirmed the relationship between compounds and target proteins. The potential molecular mechanism of ZJP predicted by network pharmacology analysis was confirmed in PLGC rats. ZJP downregulated IL-6, TNF-α, c-myc, p-MEK1 and p-ERK1/2, effectively reversing the progression of PLGC.
Conclusion: ZJP can reverse MNNG-induced PLGC, potentially through inhibition of the MEK/ERK/c-myc pathway and regulation of cellular proliferation and apoptosis.

Keywords: precancerous lesions gastric cancer, Zuojin Pill, network pharmacology, molecular dynamics simulations, ERK