Inhibition of Dyrk1a attenuates type 1 diabetic cardiomyopathy via anti-ferroptosis

Abstract

Diabetic cardiomyopathy (DCM) is a major complication of type 1 diabetes mellitus (T1DM) with limited treatment options. Dyrk1a is involved in multiple diseases, comprising neurodegenerative disorders, cancer and diabetes. In addition, Dyrk1a is an emerging therapeutic target. Nonetheless, it remains ambiguous with regard to its role in T1DM-related DCM. The present study investigated the function and mechanisms of Dyrk1a in DCM. Experimental T1DM was induced through sequential low-dose streptozotocin administrations via intraperitoneal delivery. The investigation showed conspicuous cardiac upregulation of Dyrk1a protein expression in this T1DM murine model. Pharmacological intervention was performed by employing the Dyrk1a-targeting compound harmine, administered through oral gavage, which ameliorated cardiac dysfunction characteristic of DCM. This therapeutic efficacy was mechanistically linked to ferroptosis inhibition, which was established through harmine-mediated attenuation of pathological signatures, namely reduced malondialdehyde accumulation, enhanced glutathione bioavailability, as well as elevated expression of ferroptosis regulators SLC7A11 and GPX4. It is noteworthy that co-administration of the ferroptosis activator erastin nullified the cardioprotective properties of harmine. Together, these findings establish harmine as an effective modulator of ferroptosis pathways, conferring protection against hyperglycemia-induced cardiomyocyte injury. Dyrk1a inhibition enhances cardiac function in T1DM by reducing ferroptosis.