Dapagliflozin attenuates diabetic cardiomyopathy via NRF2 protein upregulation-driven glutathione synthesis to inhibit myocardial ferroptosis

Aims: Ferroptosis has emerged as a critical pathological mechanism contributing to the development and progression of type 2 diabetic cardiomyopathy (DCM). Dapagliflozin (DAPA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i) with established cardiovascular benefits, however, DAPA's efficacy in modulating Ferroptosis during type 2 DCM remains to be elucidated.

Methods and fundings: In vivo, using a spontaneously diabetic Goto-Kakizaki (GK) rat model, we conducted proteomic profiling revealing distinct myocardial Ferroptosis signatures associated with dysregulated glutathione metabolism across normal control, GK and GK + DAPA groups. Subsequent validation demonstrated characteristic Ferroptosis markers in diabetic myocardium, including elevated Fe²⁺ level, increased Fe³⁺ deposition, heightened malondialdehyde (MDA)-mediated lipid peroxidation, and ultrastructural mitochondrial aberrations. DAPA administration (5 mg/kg/d) significantly restored glutathione homeostasis, mitigated myocardial Ferroptosis and remodeling and enhanced cardiac function. This effect correlated with upregulated expression of Ferroptosis regulators: NRF2, SLC7A11, GPX4 and FTH-1 proteins. Cardiomyocyte-specific AAV9-mediated Nrf2 overexpression and pharmacological interventions (erastin/ferrostatin-1) identified NRF2 as the key mediator of DAPA's anti-ferroptotic action. Notably, DAPA rescued erastin-induced Ferroptosis in DCM. In vitro, validation using high glucose-stimulated H9C2 cardiomyocytes replicated the ferroptotic phenotype, showing iron overload, MDA and lipid ROS elevation, and mitochondrial depletion. Genetic Nrf2 silencing, genetic Gpx4 silencing or erastin treatment exacerbated these effects, while both DAPA (10μM) and ferrostatin-1 (10 μM) demonstrated comparable Ferroptosis inhibition.

Significance: DAPA attenuates type 2 DCM via NRF2 protein upregulation-driven glutathione synthesis to inhibit myocardial Ferroptosis, identifying upregulation of NRF2 as a promising therapeutic target for Ferroptosis intervention in type 2 DCM.

Dapagliflozin; Diabetic cardiomyopathy; Glutathione metabolism; Myocardial ferroptosis; NRF2.