Cross-regulatory mechanisms linking ferroptosis, epigenetics, and circadian rhythm to mitochondrial quality control in diabetic cardiomyopathy

• This review delineates the multifaceted mechanisms of mitochondrial quality control (MQC) in diabetic cardiomyopathy (DCM), integrating mitochondrial dynamics, mitophagy, and biogenesis with emerging regulatory networks. • It emphasizes cross-talk between ferroptosis, epigenetic modifications, and circadian rhythm disruption in modulating mitochondrial homeostasis under diabetic stress. • Novel insights are provided into the roles of non-coding RNAs, post-translational modifications, and mitochondrial–immune interactions in MQC disruption and DCM pathogenesis. • The review summarizes current pharmacological and non-pharmacological interventions targeting key nodes of MQC, including AMPK, SIRT1/3, PGC-1α, and antioxidant pathways. • By highlighting integrated therapeutic strategies, this review proposes a cross-regulatory framework for restoring mitochondrial function and offers future perspectives for precise MQC-targeted interventions in DCM. Diabetic cardiomyopathy (DCM) is a distinct cardiac disorder that develops independently of coronary artery disease and hypertension. Mitochondrial dysfunction is widely recognized as a hallmark pathological feature of DCM. Effective mitochondrial quality control (MQC) is critical for preserving cardiomyocyte metabolism and contractile performance, and its disruption substantially contributes to both disease initiation and progression. We synthesize current evidence on disruptions of MQC in diabetic cardiomyopathy. The spectrum covers imbalanced fission–fusion dynamics, attenuated mitochondrial biogenesis, compromised mitophagy, disturbed Ca 2+ homeostasis, heightened ferroptotic vulnerability, loss of proteostasis, and epigenetic dysregulation. We emphasize the intricate cross-talk among these processes, which collectively exacerbate mitochondrial deterioration and myocardial injury. Building on these mechanistic insights, we also summarize recent therapeutic advances targeting MQC, such as natural compounds, antidiabetic agents, and non-pharmacological approaches. These interventions show promise in modulating mitochondrial signaling and restoring homeostasis. Nevertheless, substantial barriers remain for clinical translation, including the limitations of existing experimental models, the low quality of supporting evidence, and pronounced inter-individual variability. Future research should focus on developing integrated, multi-target therapeutic strategies, particularly those addressing the regulatory roles of non-coding RNAs, epigenetic modifications, and post-translational protein regulation. Advancing these areas will be essential for establishing precise and effective MQC-targeted therapies in both preclinical and clinical contexts.