Diabetes mellitus-related coronary heart disease (DM-CHD) is the most common cause of death in diabetic patients. Various studies have shown that Chinese medicine Fufang-Zhenzhu-Tiaozhi capsule (FTZ) has therapeutic effects on cardiovascular diseases. More research is required to determine the mechanism of FTZ protection against coronary atherosclerosis.To investigate the unique mechanism of FTZ in treatment of DM-CHD minipigs with coronary atherosclerosis.High-fat/high-sucrose/high-cholesterol diet combined with streptozotocin and coronary balloon injury were used to induce DM-CHD minipig model, which was then randomly divided into: DM-CHD model, DM-CHD treated with FTZ or positive drug (Metformin + Atorvastatin, M+A). After twenty-two weeks, ultrasonography, electrocardiography, and image detection were employed to detect cardiac functions and assess coronary artery stenosis and plaque. Human umbilical vein endothelial cells (HUVECs) were treated high glucose or/and FTZ. Pigs tissues and treated-cells were collected for further testing.In DM-CHD minipigs, FTZ treatment significantly reduced disordered glycolipid metabolism similar as M+A administration. FTZ and M+A also alleviated coronary stenosis and myocardial injury. In addition, IκB and NF-κB phosphorylation levels, as well as the protein levels of IL-1β, Bax, cleave-Caspase 3, Bcl-2, and α-SMA were dramatically increased in the DM-CHD coronary artery, whereas CD31 and VE-cadherin expressions were decreased. Similar to M+A, FTZ reversed these protein levels in the DM-CHD coronary artery. Furthermore, FTZ ameliorated the damage and high migration activity of HUVECs induced by high glucose.FTZ improves coronary atherosclerosis through modulating inflammation, alleviating apoptosis, and inhibiting EndMT of coronary artery to protects against DM-CHD.Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.