A new insight into the mechanism of DEHP-induced cardiotoxicity: Triggering pyroptosis of cardiomyocytes by disrupting sphingolipid metabolism

The widespread use of di(2-ethylhexyl) phthalate (DEHP) as a plasticizer raises concerns due to its environmental persistence and cardiotoxicity. Nevertheless, the precise mechanisms through which DEHP induces cardiac damage, particularly concerning myocardial injury, remain inadequately understood. Using a mouse model, this investigation employed UPLC-MS/MS to demonstrate that exposure to DEHP significantly elevated the concentration of its primary metabolite, mono(2-ethylhexyl) phthalate (MEHP), in cardiac tissue, while DEHP itself did not exhibit a significant difference. DEHP-induced myocardial injury in mice was evidenced by disorganized myocardial fibers, Collagen deposition and elevated serum creatine kinase-MB (CK-MB) and C-reactive protein (CRP). Further analysis through database screening and experimental validation indicated that DEHP mediates myocardial injury by activating the sphingolipid metabolic pathway involving the sphingosine kinases 1 (SphK1)/ sphingosine 1-phosphate receptor 2 (S1PR2) axis. Molecular docking and cellular thermal shift assays (CETSA) confirmed that MEHP could directly bind to and enhance the stability of SphK1. DEHP exposure also increased pyroptosis-related proteins, reversible via SphK1 Inhibitor PF543 or S1PR2 siRNA. In conclusion, this study first links DEHP-induced cardiac Pyroptosis to SphK1/S1PR2 signaling in mice, providing novel insights into DEHP-associated cardiotoxicity, contributing to cardiac damage and thereby offering new theoretical insights into DEHP-related cardiac toxicity.