Molecular Mechanisms Underlying Sishen Pill Treating Depression‐Related Gastritis Based on Network Pharmacology and Experimental Verification

Background Sishen Pill (SSW) has been demonstrated to be effective in neurological and gastrointestinal disorders, while it is less emphasized in depression‐related gastritis. Methods Network pharmacology and molecular docking were performed to identify the hub targets of SSW and the underlying mechanisms in the therapy of depression‐related gastritis. In a cell experiment, by injection of LPS, GES‐1 and BV‐2 cells were used for depression and gastritis injury model construction, respectively. In a rat experiment, an ethanol and CUMS stimulated depression‐related gastritis rat model was established. The CCK‐8 assay and wound healing were used to determine the cell viability and migration, respectively. Open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were used for the detection of rat behavior. Hematoxylin−eosin (HE) staining and Alcian Blue−Periodic Acid‐Schiff (AB‐PAS) were used to detect pathological injury. Western blotting was used to detect the protein levels of AKT1 and TLR4 signaling pathway−related proteins. ELISA was used to evaluate the inflammatory factors, junction proteins, and gastric mucosa health indicators. Results Network pharmacology identified that AKT1 was the only one to be downregulated in both depression and gastritis. Function analysis indicated that AKT1 was involved in the toll‐like receptor signaling pathway. Molecular docking confirmed the well‐binding ability between AKT1 and quercetin, an effective molecule from Euodiae Fructus in SSW prescription. In both cell and rat models, AKT1 was downregulated. SSW treatment consistently restored AKT1 levels, which consequently alleviated inflammatory response, gastric mucosal lesion, and depression‐like behaviors. Moreover, these therapeutic effects were mediated through the inhibition of the TLR4 signaling pathway, as the AKT1 inhibitor MK‐2206 effectively reversed all the beneficial effects of SSW. Conclusion This study indicates the potential of SSW as a treatment for depression‐related gastritis and uncovers the underlying mechanism of targeted AKT1 related to the TLR4 pathway, providing valuable information for researchers in effective targeted therapies.