Study on the Mechanism of Huayu Xiaopi Decoction Regulating NLRP3/ASC/Caspase-1 Pathway to Inhibit Macrophage Pyroptosis and Improve Gastric Precancerous Lesions

OBJECTIVE To investigate the intervention effect and mechanism of Huayu Xiaopi decoction(HYXPD) on precancerous lesions of gastric cancer(PLGC) model rats based on the NLRP3/ASC/Caspase-1 signaling pathway.

METHODS PLGC model rats were established using a composite modeling method combining free drinking of N-methyl-N’-nitro-N-nitrosoguanidine solution, irregular feeding/fasting, ethanol gavage, and ranitidine gavage. A total of 60 model rats were randomly divided into model group, control group, and high-, medium-, low-dose HYXPD experimental groups(12 rats per group), with an additional 12 healthy rats as the blank group. The high-, medium-, and low-dose HYXPD groups were gavaged with HYXPD at doses of 24.8, 12.4, and 6.2 g·kg⁻¹, respectively The control group received 0.002 g·kg⁻¹ folic acid solution. Both blank and model groups were gavaged with an equal volume of 0.9% NaCl, once daily for 90 d. General survival status and body weight of rats in each group were observed and recorded. Pathological changes of gastric tissue were observed by HE staining and AB-PAS staining. IL-1β, IL-18 mRNA expression levels were detected by RT-qPCR. Western blotting was used to measure the protein expression levels of NLRP3, Caspase-1, ASC, and GSDMD-N. Multiplex immunohistochemistry was used to detect the expression of NLRP3 and GSDMD-N protein in macrophages of gastric tissue of rats in each group.

RESULTS Compared with the blank group, the rats in the model group exhibited a poor general survival status, a significantly reduction in body weight, and evident pathological damage in gastric tissue. Moreover, the expression of IL-1β, IL-18 mRNA, as well as the protein of NLRP3, ASC, Caspase-1 and GSDMD-N, were significantly increased in gastric tissue. Correspondingly, the expression of NLRP3 and GSDMD-N in gastric tissue macrophages was markedly increased. In contrast, all treatment groups showed significant improvements compared to the model group, including better overall health status, increased body weight, and ameliorated pathological damage in the gastric tissue. Furthermore, the expression of IL-1β, IL-18 mRNA, along with NLRP3, ASC, Caspase-1, and GSDMD-N protein in gastric tissue were significantly reduced. The expression of NLRP3 and GSDMD-N in macrophages of gastric tissue decreased significantly.

CONCLUSION HYXPD can significantly reduce gastric mucosal inflammation, block the “inflammation-cancer” transformation, effectively prevent PLGC, and its specific mechanism is related to inhibition of NLRP3/ASC/Caspase-1 pathway mediated macrophage pyroptosis.