Considered an effective supplementary therapy, traditional Chinese medicine (TCM) has been widely applied in the treatment of coronary heart disease (CHD). In this study, we aim to investigate the effects and mechanisms of Huo-Tan-Chu-Shi decoction (HTCSD, an in-hospital TCM prescription) in the treatment of CHD with the phlegm-damp syndrome in mice by non-targeted metabolomics with liquid chromatography-mass spectrometry (LC-MS)/MS.A CHD with phlegm-damp syndrome model was established with ApoE-/- mice by subcutaneous injection with isoproterenol combined with high temperature, high humidity, and a high-fat diet, and divided into the HTCSD and Tanshi groups. C57BL/6 mice were set as the control group with an ordinary environment and diet. After administration, electrocardiogram (ECG), interventricular septum thickness (IVS) and left ventricular posterior wall thickness (LVPW), serum levels of creatine phosphokinase-Mb (CK-MB), cardiac troponin T (cTnT), lactic dehydrogenase (LDH) and oxidized low-density lipoprotein (oxLDL), and myocardial histopathological changes were recorded to assess myocardial damage. LC-MS/MS was applied to demonstrate the serum metabolic profile and explore potential mechanisms.The obvious depressions of the ST segment and T wave presented in the ECG of Tanshi mice, while the depressions in ECG of HTCSD mice were significantly reduced. Compared with the control group, IVS, LVPW, and serum levels of CK-MB, cTnT, LDH, and oxLDL increased greatly in the Tanshi group, while these indicators decreased remarkably in the HTCSD group compared with those of the Tanshi group. Histopathology showed severe structural disorder, necrosis, and fibrosis of myocardial cells in Tanshi mice, which were alleviated in HTCSD mice. Metabonomics analysis showed obvious metabolic alterations among the experimental mice and revealed that the relevant metabolic pathways mainly included phospholipid metabolism, necroptosis, and autophagy.HTCSD has a certain therapeutic effect in mice with CHD with phlegm-damp syndrome via reducing myocardial ischemia, hypertrophy, and fibrosis. The underlying mechanisms involve the regulation of phospholipid metabolism, necroptosis, and autophagy.Copyright © 2022 Zhaoying Liang et al.