Integrated Lipidomic and Energy Metabolomic Analyses Reveal the Cardioprotective Mechanisms of Meconopsis horridula Alkaloids in Heart Failure

Abstract Meconopsis horridula Hook. f. & Thomson (MH) is a traditional Tibetan medicinal herb used to promote blood circulation and treat cardiovascular disorders; however, its active constituents and cardioprotective mechanisms in heart failure (HF) remain poorly understood. In this study, liquid chromatography–mass spectrometry was used to characterize the alkaloid profile of MH, and the cardioprotective effects of its alkaloid fraction were evaluated in a doxorubicin-induced rat model of HF. A total of 26 alkaloids were identified. Treatment with MH alkaloids significantly improved cardiac function and attenuated myocardial injury in HF rats. To elucidate the underlying mechanisms, quantitative lipidomics and targeted energy metabolomics analyses were performed. Compared with the model group, MH treatment altered multiple lipid and energy metabolites associated with ether lipid metabolism, glycerophospholipid metabolism, lipid and atherosclerosis, glyoxylate and dicarboxylate metabolism, and the citrate cycle. Integrated pathway analysis identified NADH/ubiquinone oxidoreductase complex assembly factor 6 (NDUFAF6), AMPK, ACC, GLUT4, ACOT1, and ATP2A as key regulatory nodes. Western blot analysis further supported the involvement of these proteins in MH-mediated metabolic remodeling. Collectively, these findings suggest that MH alkaloids alleviate HF by partially restoring dysregulated glucose and lipid metabolism and provide mechanistic insights into their cardioprotective effects.