Abstract

Gastric mucosal injury refers to the pathological changes characterized by congestion, edema, bleeding and erosion of the gastric mucosa caused by various factors. This condition is a significant feature of gastritis in which the inflammatory response plays a critical role in its pathogenesis. The herbal pair Daphniphyllum calycinum – Polygonum hydropiper (DCPH), known for its anti‐inflammatory and antioxidant properties, has been shown to alleviate gastric mucosal injury. This study aimed to elucidate the mechanism by which DCPH alleviates gastric mucosal injury by integrating network pharmacology with both in vivo and in vitro experimental validation. The results indicated that DCPH treatment significantly increased the antioxidant capacity of the cells and decreased the expression of inflammation‐related factors. DCPH suppressed macrophage M1 polarization while inducing apoptosis in damaged cells. Furthermore, DCPH diminished structural gastric mucosal damage and gastric inflammation. DCPH promotes autophagy by upregulating the expression of LC3II/I and Beclin1, and downregulating P62 accumulation, thereby inhibiting the TLR4/NF‐κB/NLRP3 signaling pathway and M1 polarization, and reducing the release of inflammatory factors. However, these effects can be reversed by the autophagy inhibitor chloroquine (CQ). In conclusion, DCPH alleviates gastric mucosal injury via regulating autophagy and targeting TLR4/NF‐κB/NLRP3, thereby offering insights for the treatment of gastrointestinal diseases. The schematic diagram illustrated the proposed mechanism of DCPH in mouse macrophages. DCPH promotes autophagy to suppress the TLR4/NF‐κB/NLRP3 pathway and M1 polarization, thereby attenuating cellular oxidative stress and inflammation.