WTAP-regulated m⁶A modification contributes to cuproptosis in cardiomyocytes and diabetic cardiomyopathy

Cuproptosis is a recently identified form of regulated cell death triggered by intracellular copper (Cu) overload. Diabetic conditions are characterized by disrupted Cu homeostasis. This study reveals a critical mechanistic link between the RNA methyltransferase WTAP and hypoxia-inducible factor-2α (HIF-2α) in promoting cardiomyocyte cuproptosis in diabetic cardiomyopathy (DCM). In both diabetic mouse hearts and high-fat/high-glucose plus Cu chloride-treated AC16 cardiomyocytes, elevated levels of WTAP and HIF-2α were observed alongside increased cuproptosis. Mechanistically, WTAP facilitates m⁶A-dependent upregulation of HIF-2α, which transcriptionally activates the divalent metal transporter 1 (DMT1). Enhanced DMT1 expression leads to intracellular Cu accumulation, subsequently inducing cuproptosis and driving DCM progression. Importantly, the clinically used agent dexmedetomidine (DEX) was found to alleviate DCM in vivo, at least in part, by suppressing DMT1 expression and thereby inhibiting cuproptosis. These findings identify the WTAP/HIF-2α/DMT1 axis as a key regulator of Cu overload and cuproptosis in DCM, highlighting its therapeutic potential.