HILIC-MS-based metabolomics reveal that Astragalus polysaccharide alleviates doxorubicin-induced cardiomyopathy by regulating sphingolipid and glycerophospholipid homeostasis

• HILIC-MS was established to profile polar metabolome related with DOX cardiomyopathy. • 22 polar serum metabolites related with DOX cardiomyopathy were identified. • Sphingolipid and glycerophospholipid metabolism were the target pathways for ASP. • The levels of aSMase, AC and PLA2 and SMS1 were validated by western blot. Doxorubicin (DOX) is widely used against cancer but carries the risk of a progressive cardiomyopathy. Astragalus polysaccharides (ASP) is the main active ingredient of Astragalus membranaceus Bunge. It has been proved to be effective against DOX-induced cardiomyopathy. However, its therapeutic mechanism is not yet well explored. In this study, a metabolomics approach based on hydrophilic interaction liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HILIC-Q-TOFMS) was developed to characterize the metabolic fluctuations associated with DOX cardiomyopathy and elucidate the underlying mechanisms of the protective effects of ASP. By the combination of HILIC-Q-TOFMS and multivariate and univariate data analysis, we identified 22 polar serum metabolites associated with DOX cardiomyopathy, 12 of which were significantly reversed when the animals were co-treated with ASP through two main metabolic pathways, i.e., sphingolipid and glycerophospholipid metabolism. Furthermore, it was found that ASP could alleviate DOX-induced cardiomyopathy by decreasing the levels of acid sphingomyelinase, acid ceramidase and phospholipase A2 and increasing the levels of sphingomyelin synthase to regulate the sphingolipid and glycerophospholipid metabolic disorder. These results revealed that sphingolipid and glycerophospholipid metabolism may be significantly responsible for DOX cardiomyopathy, which is also a major mechanism for the action of ASP against DOX cardiomyopathy.