Regulation of ferroptosis and mitochondrial homeostasis disruption in diabetic cardiomyopathy: Therapeutic potential of traditional Chinese medicine

Abstract

Diabetic cardiomyopathy (DCM) is a common diabetes-related complication that can progress to heart failure. Early-stage DCM is asymptomatic, requiring advanced imaging for diagnosis, and currently lacks approved targeted therapies, highlighting the urgent need for DCM-specific drugs. Emerging evidence suggests that iron homeostasis imbalance and mitochondrial dysfunction are closely interconnected and synergistically drive DCM onset and progression. This review provides a comprehensive overview of the molecular interplay between ferroptosis and mitochondrial damage in DCM and evaluates the therapeutic potential of three intervention categories: (1) Standard glucose-lowering agents; (2) Novel mechanism-targeted therapies (iron chelators, mitochondrial protectants); and (3) Multi-targeting traditional Chinese medicine (TCM) and their bioactive compounds. While Sodium-glucose co-transporter-2 inhibitors and other antidiabetic drugs provide modest protection against DCM progression, they exhibit limited efficacy, do not fully restore mitochondrial function, and are associated with adverse effects. Emerging targeted therapies such as iron chelators and mitochondrial protectants face safety concerns and lack extensive clinical validation, with their potential drug-drug interactions remaining uncertain. In contrast, selected TCM-derived bioactive compounds have shown cardioprotective potential through multi-target regulation of ferroptosis and mitochondrial homeostasis in preclinical DCM models. Additional TCM with demonstrated efficacy in ferroptosis and mitochondrial function are also reviewed. Given the multifactorial nature of DCM, combination therapies targeting ferroptosis and mitochondrial dysfunction may offer superior outcomes. Future drug development should prioritize agents - whether synthetic or natural - that precisely regulate these interrelated pathways, enabling personalized treatment strategies for DCM.

Keywords: Diabetic cardiomyopathy; Ferroptosis; Mitochondrial dysfunction; Iron metabolism; Multi-target therapy

Core Tip: Diabetic cardiomyopathy (DCM) is often clinically silent until heart failure develops, and disease-specific therapies remain unavailable. This review examines the interaction between ferroptosis and mitochondrial dysfunction in DCM, linking iron dyshomeostasis, reactive oxygen species overload, impaired antioxidant defenses, and disrupted mitochondrial quality control. We compare evidence and limitations of glucose-lowering drugs, mechanism-targeted approaches (iron chelators and mitochondrial protectants), and multi-target traditional Chinese medicine and bioactive compounds. We propose that combination strategies co-targeting ferroptosis and mitochondrial pathways, particularly multi-target traditional Chinese medicine and its bioactive compounds, may offer a promising approach for more effective and individualized DCM treatment.