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

Table 1 Summary of standard glucose-lowering agents and novel mechanism-targeted therapies that have demonstrated cardioprotective effects in diabetic cardiomyopathy or diabetes-associated cardiac injury

Drug	Drug dosage	Model	Mechanisms
Canagliflozin	20 mg/kg/day, i.g., 6 weeks; 10 μM, 24 hours	C57BL/6J mice; H9C2 cells under high glucose (35 mmol/L)	↓oxidative stress & ferroptosis markers; ↓total iron & Fe²+ deposition; improves cardiac injury indices (DCM protection); ↓ROS/Lipid ROS; ↑ΔΨm; ↓iron overload/ferroptosis-related injury[112]
Canagliflozin	10 or 30 mg/kg/day, i.g., 12 weeks; 5 μg/mL, 24 hours (with PA 0.1 mmol/L)	C57BL/6J mice; HL-1 cardiomyocytes lipotoxicity model	Activates PINK1-Parkin-dependent mitophagy; improves mitochondrial function (via AMPK phosphorylation noted)[114]; Activates AMPK; inhibits inflammation (COX-2/iNOS) and ferroptosis indicators in PA-treated cells[113]
Evogliptin	100 mg/kg/day, i.g., 12 weeks	db/db mice	Improves systolic/diastolic function; reduces lipotoxicity; activates PGC-1α/NRF1/TFAM → mitochondrial biogenesis[117]
Liraglutide	200 μg/kg/day (subcutaneous), 8 weeks	Diabetic rat model	Activates Nrf2/GPX4 signaling; ↓lipid peroxidation and ferroptosis-related myocardial injury[120]
Melatonin	20 mg/kg/day, i.g., 4 weeks; 100 μmol/L, 4 hours	Parkin-/- mice (C57BL/6 background)-DCM model; Primary neonatal cardiomyocyte culture	Promotes Parkin translocation to mitochondria; increases LC3-II expression; enhances PINK1/Parkin-dependent mitophagy[130]
Alisporivir	2.5 mg/kg/day, i.p., 20 days	C57BL/6NCrl line-DM model	Induces mitophagy via transcriptional upregulation of PINK1 and Parkin; reduces mitochondrial lipid peroxidation in Diabetic mouse heart tissue[131]
mito-TEMPO	0.7 mg/kg/day, i.p., 30 days. 25 nmol/L, 24 hours	T1DM (C57BL/6 mice) and T2DM mouse (db/db mice) models; Adult mouse ventricle cardiomyocytes	Mitochondria-targeted ROS scavenger; reduces oxidative stress; prevents cardiomyocyte apoptosis and cardiac hypertrophy[132]
MitoGamide	10 mg/kg, i.g., 10-12 weeks	Akita diabetic mice; Diabetic mouse heart	Mitochondria-targeted scavenging of MGO; reduced AGE formation; preservation of mitochondrial function and cardiac energetics; mitigation of oxidative stress[135,136]

i.p.: Intraperitoneal injection; i.g.: Intragastric administration; DCM: Diabetic cardiomyopathy; ROS: Reactive oxygen species; ΔΨm: Mitochondrial membrane potential; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; MGO: Methylglyoxal; AGE: Advanced glycation end-product.