Our study reveals a complex molecular cascade in type 2 diabetes mellitus (T2DM) cardiomyopathy, wherein hyperglycemia triggers a robust DNA damage response (DDR) that activates the DNA-PK complex—comprising PRKDC, XRCC5, and XRCC6—to drive endothelial ferroptosis and worsen microvascular dysfunction and cardiac decline. Here, XRCC5 is linked to type 2 diabetes mellitus.