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Xiaoyun Zou,1 Minmin Wei,2 Shouning Jia,3 Yongfu Qi,3 Hailing Li,4 Yan Liu,5 Junru Li6 1Department of Hepatopathy, Qinghai Provincial Hospital of Traditional Chinese Medicine, Xining, 810000, People’s Republic of China; 2Department of Cardiology, Qinghai Provincial Hospital of Traditional Chinese Medicine, Xining, 810000, People’s Republic of China; 3Department of Research Institute of Traditional Chinese Medicine, Qinghai Provincial Hospital of Traditional Chinese Medicine, Xining, 810000, People’s Republic of China; 4Department of Pharmacy, Qinghai Provincial Hospital of Traditional Chinese Medicine, Xining, 810000, People’s Republic of China; 5Medical College, Qinghai University, Xining, 810016, People’s Republic of China; 6Department of Spleen and Stomach Diseases, Qinghai Provincial Hospital of Traditional Chinese Medicine, Xining, 810000, People’s Republic of ChinaCorrespondence: Junru Li, Department of Spleen and Stomach Diseases, Qinghai Provincial Hospital of Traditional Chinese Medicine, Xining, 810000, People’s Republic of China, Email mlqinghai201314@sina.comObjective: Chronic gastritis, with the liver-stomach disharmony (CG-LSD) type being particularly common, is a prevalent digestive disorder. The Chinese herbal prescription “Wei-Mi-Shu (WMSP)” demonstrated positive therapeutic outcomes in clinical practice for CG-LSD. This study aimed to verify the therapeutic effect of WMSP on CG-LSD and reveal its molecular mechanism based on IL-6/STAT3 pathway.Methods: Network pharmacology analysis was employed to predict the target genes of WMSP for CG. Following this, a CG-LSD rat model was treated with WMSP, and the changes in body weight, syndrome score, and motor ability were analyzed. The gastric mucosal damage was examined by HE, AB-PAS, and scanning electron microscopy. Serum levels of inflammatory factors and mucosal injury factors were measured via ELISA. Apoptosis was evaluated by TUNEL staining, and the protein expression related to apoptosis and the IL-6/STAT3 pathway was determined by WB. Additionally, a Helicobacter pylori (H. pylori)-infected GES-1 cell model was established to measure cell activity, inflammatory factors levels, and IL-6/STAT3 pathway activation.Results: Network pharmacology identified 674 common targets between WMSP and CG, including key genes such as TP53, AKT1, TNF, IL-6, and STAT3. In CG-LSD rat models, WMSP significantly improved general health (body weight, symptoms, motor ability), suppressed serum inflammatory factors, and ameliorated gastric mucosal damage (P< 0.05). And it specifically up-regulated the expressions of PG I, GAS17, PGE2, sIgA, and GSH, while down-regulated the expressions of PG II, NOS, ET, GSSG (P< 0.05). Furthermore, WMSP inhibited gastric mucosal cell apoptosis by regulating Bcl-2/Bax (P< 0.05), and suppressed the IL-6/JAK/STAT3 pathway (P< 0.05). In H. pylori-infected GES-1 cell, WMSP enhanced cell viability, and inhibited inflammation and IL-6/JAK/STAT3 activation (P< 0.05). Critically, the protective effects of WMSP on the H. pylori-induced GES-1 cell were inhibited by a STAT3 activator (P< 0.05).Conclusion: WMSP alleviated inflammation, apoptosis, and mucosal injury in CG-LSD by targeting the IL-6/STAT3 axis.Keywords: Wei-Mi-Shu prescription, chronic gastritis with liver- stomach disharmony, inflammatory response, IL-6/STAT3 pathway