Abstract: 　　AIM: To investigate the effect and mechanism of Tianxiangdan (TXD) capsules on atherosclerosis (AS) by regulating GPER (G protein-coupled estrogen receptor) to inhibit NLRP3 inflammasome-mediated pyroptosis.
　　METHODS: Atherosclerosis models were established in APOE-/- mice through a high-fat diet, followed by randomization into groups: blank control (Control), AS model group (AS), atorvastatin group (ATV), high, medium, and low-dose TXD groups (TXD-H, TXD-M, TXD-L), and TXD+GPER inhibitor group (G15). Each treatment group received corresponding doses of TXD capsules via gavage, while other groups received respective control treatments. G15 inhibitor was administered via intraperitoneal injection for 14 weeks. Serum levels of TG, TC, LDL-C, HDL-C, TNF-α, IL-1β, and IL-18 were measured. Histopathological structure and lipid distribution were observed through HE staining and Oil Red O staining of aortic tissue. Immunofluorescence co-staining of GPER/NLRP3 was performed to examine their co-expression. Western blot was used to detect the expression of GPER, NLRP3, and pyroptosis-related protein GSDMD. RESULTS: In mice of the AS group, serum levels of TC, TG, LDL-C, HDL-C, TNF-α, IL-1β, and IL-18 were higher, and aortic lumen stenosis and lipid deposition rates were increased. Compared with the AS group, after intervention with different doses of TXD capsules, serum levels of TG, TC, LDL-C, TNF-α, IL-1β, and IL-18 were significantly reduced (P<0.01), with HDL-C levels increased in the TXD-H group (P<0.05); plaque area and lipid deposition rate were markedly decreased (P<0.05); GPER/NLRP3 fluorescence colocalization was increased. Western Blot results showed that TXD capsules increased GPER expression (P<0.05) and reduced NLRP3 and GSDMD expression (P<0.01). The G15 inhibitor reversed the effects of the Tianxiangdan capsules. CONCLUSIONTXD capsules may inhibit NLRP3-mediated pyroptosis by upregulating GPER expression, reducing inflammatory responses in the AS microenvironment, and exerting vascular protective effects.Keywords: Atherosclerosis; Pyroptosis; GPER/NLRP3 signaling pathway; Tianxiangdan capsules