To investigate whether Xuguan Ruanhua Pill（血管软化丸）can improve atherosclerosis in APOE-/-mice by regulating the AMP-activated protein kinase（AMPK）/NOD-like receptor thermal protein domain associated protein 3（NLRP3）pathway and inhibiting cellular death.

Ten C57BL/6Jmicewere used as blank control group. Sixty apolipoprotein E knockout（APOE-/-）micewere random ly divided intomodel group，Xuguan Ruanhua Pill low-dose group，Xuguan Ruanhua Pill high-dose group，atorvastatin group，Xuguan Ruanhua Pill high dose＋AMPK inhibitor combination group and AMPK inhibitor group，and were given high-fatdiet to constructatherosclerosis（AS）mousemodel for18 weeks and were given different methods of intervention in the 13th week. Differentmethods of intervention were given，and the sampleswere taken 6 weeks after the intervention，and the levels of triglyceride（TG），total cholesterol（TC），low density lipoprotein-eholesterol（LDL-C）and high density lipoprotein-eholesterol（HDL-C）were detected respectively in each group. The pathological and morphological changes ofmouse aortic tissues were observed by HE and Oil Red O staining. The levels of interleukin（IL）-1βand IL-18 in aortic tissueswere determined by ELISA，and the protein expressions of AMPK，P-AMPK，NLRP3，Cleaved-Caspase1 and GSDMD-N were detected byWestern Blot. The P-AMPK and NLRP3 protein distribution in the aortic rootwas detected by immunofluorescencemethod and transmission electron microscopy was used for the observation of aortic endothelial ultrastructural changes.

Compared with those in the control group，themodel group had significantly higher serum levels of TG，TC and LDL-C，significantly lower HDL-C levels（P<0.01），disorganised cellarrangement in the aortic rootand obvious fat vacuoles，significant atheromatous plaque deposition in the aorta，significantly lower levels of P-AMPK protein expression，and significantly lower levels of NLRP3，Cleaved-Caspase 1 and GSDMD-N proteinswere significantly increased（P<0.05 or P<0.01）. Compared with those of themodel group，the lipid disorderswere improved in the high and low dose groups of Xuguan Ruanhua Pill and the atorvastatin group，and the degree of aortic tissue and cytopathic lesions were reduced，with a significant increase in the expression level of P-AMPK，and a significant decrease in the expression levels of NLRP3，Cleaved-Caspase 1 and GSDMDN proteins（P<0.05 or P<0.01）. The expression levels were significantly reduced（P<0.05 or P<0.01），and the levels of IL-1βand IL-18 were significantly reduced（P<0.05 or P<0.01）. Compared with those of the Xuguan Ruanhua Pill high dose＋AMPK inhibitor group，the level of coagulopathy-associated proteins in the Xuguan Ruanhua Pill high-dose group was significantly reduced（P<0.05 or P<0.01），and the degree of damage to aortic endothelial cells was attenuated，while that in the AMPK inhibitor group in contrast.

Xuguan Ruanhua Pillmay exert a protective effect on atherosclerotic mice by regulating the AMPK/NLRP3 pathway to reduce cell death.