The Chinese Herbal Medicine Li Qi Huo Xue Di Wan Ameliorates Ischemia or Hypoxia‐Induced Cardiac Injury and Remodeling in the Heart Through a Mechanism Involving Reduction of Necroptosis

ABSTRACT Li Qi Huo Xue Di Wan (LQHXDW), a Chinese herbal medicine, is commonly used to treat symptoms such as palpitations, chest tightness, chest pain, and shortness of breath. However, its potential to reduce ischemia or hypoxia‐induced cardiac injury and remodeling, along with the precise mechanisms involved, remains unclear. This study aims to investigate the effects of LQHXDW on cardiac injury and remodeling induced by ischemia or hypoxia, both in vivo and in vitro, and to elucidate the underlying mechanisms. The mouse heart was subjected to ischemia for 14 days, showing evident myocardial injury and notable cardiac remodeling, accompanied by a reduction in cardiac function; these phenomena were reversed in the presence of LQHXDW. In the cultured cardiomyocyte exposed to hypoxia, incubation with LQHXDW increased the cell viability and reduced lactate dehydrogenase release. Mechanistically, LQHXDW exerted inhibitory effect on the phosphorylation levels of RIPK1, RIPK3, and MLKL as well as oxidative stress in the mice hearts suffered ischemia and the cultured cardiomyocytes exposed to hypoxia. Using the methods of ultra‐high performance liquid chromatography‐quadrupole time‐of‐flight‐mass spectrometry, network pharmacology, and cellular thermal shift assay, phenethyl caffeate and isoliquiritigenin were identified as the potential active compounds in LQHXDW that counteract necroptosis. Based on these observations, we conclude that LQHXDW protects the heart against ischemia or hypoxia‐induced cardiac injury and remodeling through suppression of the RIPK1/RIPK3/MLKL pathway‐dependent necroptosis and oxidative stress.