Artemisinin Protects Diabetic Cardiomyopathy by Inhibiting Ferroptosis via Upregulating Nrf2/NQO1 and GPX4 Pathways

Diabetic cardiomyopathy (DCM), a major lethal complication of diabetes, involves ferroptosis as a key pathogenic mechanism. Meanwhile, studies on the cardioprotective effect of artemisinin (Art) are mostly superficial, its specific mechanisms and whether it is related to ferroptosis is unclear. This study investigated Art's cardioprotective effects against DCM-associated ferroptosis through in vitro and in vivo models. In high glucose-treated H9c2 cardiomyocytes, Art significantly reduced reactive oxygen species (ROS) and Fe²⁺ levels while preserving mitochondrial function. In streptozotocin (STZ)-induced diabetic mice, 8-week Art treatment improved cardiac function, attenuated histopathological damage, and normalized serum markers (CK, LDH, TG, and TC). Art restored redox balance by increasing glutathione (GSH) while decreasing MDA and Fe²⁺, and reversed DCM-induced protein expression changes: upregulating GPX4, HO-1, Nrf2, and NQO1 while downregulating TfR and P53. Both Art and ferroptosis inhibitor Fer-1 demonstrated comparable protective effects, confirming Art's action through ferroptosis inhibition. These findings establish Art as a promising therapeutic candidate for DCM via modulation of the Nrf2/GPX4 pathway and iron homeostasis.