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.

Table 2 Traditional Chinese medicine-derived bioactive compounds that ameliorate mitochondrial homeostasis disruption and ferroptosis

Compounds	Herb source	Drug dosage	Model	Mechanisms	Clinical evidence
Resveratrol	Japanese knotweed, Reynoutria japonica Houtt.	25-50 mg/kg i.g./i.p. (5-7 days); 20-50 μM in vitro	STZ-DCM mice; HG-H9c2 cells	Activating SIRT1 → PGC-1α increases mitochondrial biogenesis (↑mtDNA, ΔΨm, ATP). Additionally, activating the Nrf2-GPX4 axis confers anti-ferroptotic protection; in STZ-T1DM DCM mice, resveratrol (25 mg/kg/day, 12 weeks) ↓labile Fe/MDA, ↑GSH/GPX4, improved EF/FS, and restored mitochondrial ultrastructure[95,139,140]	Clinical studies and systematic reviews report improved insulin resistance, glycemic control, and oxidative stress (15 RCTs, 896 patients)[142-145]
Salidroside	Rhodiola, Rhodiola rosea L.	1.5 g/kg/day i.g. for 5 weeks	db/db mice	Inhibits ferroptosis (↑GPX4; ↓serum iron, transferrin; trend ↓SLC7A11); modulates autophagy (↓LC3-II); improves myocardial ultrastructure[146]
Salidroside	Rhodiola, Rhodiola rosea L.	50-100 mg/kg/day, 16 weeks (oral gavage); 10 μM in vitro	HFD/STZ-DCM mice; NRCMs	Activates AMPK/Akt-SIRT3 → ↑PGC-1α, TFAM; promotes mitochondrial biogenesis; improves mitochondrial function[147]

i.p.: Intraperitoneal injection; i.g.: Intragastric administration; DCM: Diabetic cardiomyopathy; ΔΨm: Mitochondrial membrane potential; T1DM: Type 1 diabetes mellitus; GSH: Glutathione; STZ: Streptozotocin; RCT: Randomized clinical trial; HFD: High-fat diet.

Table 3 Effects of traditional Chinese medicine-derived bioactive compounds on regulating mitochondrial dynamics in diabetic cardiomyopathy

Compounds	Herb source	Drug dosage	Model	Mechanisms
Ginsenoside Rb1	Ginseng, Panax ginseng C. A. Meyer	50 mg/kg/day i.g.; 50-100 μM in vitro	db/db mice; PA-H9c2 cells	Upregulates Mfn2; promotes mitochondrial fusion; reduces oxidative stress and apoptosis; improves mitochondrial function[148]
Ophiopogon D	Dwarf lilyturf, Ophiopogon japonicus (Thunb.) Ker Gawl.	5 mg/kg/day i.g. for 4 weeks; 1 μM, 5 μM, 10 μM in vitro	db/db mice; PA-H9c2 cells	Inhibits Drp1, restores MFN1/2 and OPA1; improves mitochondrial dynamics, reduces apoptosis, relieves lipotoxic injury[149]
Paeonol	Cortex Moutan, Paeonia suffruticosa Andr.	75 mg/kg/day, 150 mg/kg/day, 300 mg/kg/day i.g.; 25 μM, 50 μM, 100 μM, 200 μM in vitro	STZ-DCM rats; HG-primary cardiomyocytes	Activates CK2α-Stat3 pathway; upregulates Opa1; promotes mitochondrial fusion; inhibits oxidative stress; improves cardiac function[150]
Perillaldehyde	Perilla, Perilla frutescens (L.)	100 mg/kg/day, 200 mg/kg/day i.g., 20 μM in vitro	STZ-DCM rats; HG-H9c2 cells	Upregulates miR-133a-3p, inhibits GSK-3β; suppresses fibrosis (Col-I, Col-III, α-SMA); reduces apoptosis; improves mitochondrial dynamics (fusion/fission balance)[151]
Punicalagin	Pomegranate, Punica granatum L.	30 mg/kg/day, 90 mg/kg/day i.g., 10 μM in vitro	STZ-DCM rats; HG-H9c2 cells	Inhibits PTP1B activity, increases Stat3 phosphorylation, upregulates Opa1, promotes mitochondrial fusion, improves mitochondrial function[152]
Rhein	Rhubarb (Rheum palmatum L.)	120 mg/kg/day i.g.; 1 μg/mL in vitro	HFD/STZ-DCM mice; HG-NRCMs; H9c2 ClpP-KD	Improves mitochondrial dynamics (↓p-Drp1S616/Drp1, ↑Opa1, Mfn1, Mfn2); reduces apoptosis (↓caspase-9, cleaved caspase-3, Bax; ↑Bcl2); inhibits hypertrophy (↓ANP, BNP, β-MHC); normalizes ClpP expression[153]

i.g.: Intragastric administration; DCM: Diabetic cardiomyopathy; STZ: Streptozotocin; HFD: High-fat diet.

Table 4 Effects of traditional Chinese medicine-derived bioactive compounds on regulating mitophagy in diabetic cardiomyopathy

Compounds	Herb source	Drug dosage	Model	Mechanisms
Fucoxanthin, FX	Brown seaweed, Undaria pinnatifida (Harvey) Suringar	200 mg/kg/day, 1 μM in vitro	STZ-induced DCM rats; HG-treated H9c2 cells	Alleviates oxidative stress; restores mitophagy; reduces myocardial fibrosis and hypertrophy[154]
Heterophyllin B	Prince ginseng, Pseudostellaria heterophylla (Miq.) Pax	8 mg/kg/day, 20 mg/kg/day, 0.1 μM, 0.5 μM, 1 μM, 5 μM, 10 μM, 50 μM, 100 μM in vitro	STZ-DCM mice; HG-H9c2 cells; HG-NRCMs	MAVS-mediated mitochondrial homeostasis; normalizes mitophagy/autophagic flux (LC3-II balanced, autolysosome↓); ↑OPA1 → fusion↑/fragmentation↓; mitochondrial ROS↓[155]
Tanshinone IIA	Red sage (Danshen), Salvia miltiorrhiza Bunge	10 mg/kg/day, 25 mg/kg/day	STZ-induced DCM rats	Enhances PINK1-Parkin-dependent mitophagy (↑PINK1, Parkin, Beclin-1, LC3II/I; ↓p62); increases LC3-COX IV colocalization; restores mitochondrial ultrastructure & function; improves cardiac function; lowers blood glucose[156]

DCM: Diabetic cardiomyopathy; STZ: Streptozotocin.

Table 5 Effects of traditional Chinese medicine-derived bioactive compounds on regulating mitochondrial biogenesis in diabetic cardiomyopathy

Compounds	Herb source	Drug dosage	Model	Mechanisms
Ferulic acid	Angelica, Angelica sinensis (Oliv.) Diels	25 mg/kg/day i.g.; 10-25 μM in vitro	HFD + HFru + STZ DCM rats; HG-H9c2	Normalizes MAM (↓PACS2/IP3R2/FUNDC1/VDAC1); restores mitochondrial biogenesis, fusion & OxPhos[157]
Gypenosides	Gynostemma, Gynostemma pentaphyllum (Thunb.) Makino	50 mg/kg/day, 100 mg/kg/day, 150 mg/kg/day (10 weeks, oral)	STZ-induced diabetic rats	Activates AMPK/Nrf2/HO-1 pathway; ↑ PGC-1α expression; enhances antioxidant defense; promotes mitochondrial biogenesis; improves cardiac function[158]
Icariin	Epimedium, Epimedium spp.	30 mg/kg/day, 7.5 μmol/L, 15 μmol/L, 30 μmol/L (in vitro)	db/db mice; HG-treated primary neonatal mouse cardiomyocytes	Activates Apelin/Sirt3 signaling → ↑ mitochondrial proteins (PGC-1α, Mfn2, Cyt-b) → restores ΔΨm, reduces ROS, inhibits apoptosis, improves cardiac function[96]
Rosmarinic acid	Rosemary, Rosmarinus officinalis L.	100 mg/kg/day (4 weeks, oral gavage)	STZ-induced DCM mice; HG-treated H9c2 cardiomyocytes	Activates SIRT1/PGC-1α pathway; improves mitochondrial function (↑ΔΨm, ↑ATP, ↓ROS); reduces apoptosis (↓cleaved caspase-3, ↓Bax; ↑Bcl2); ameliorates cardiac dysfunction[159]

i.g.: Intragastric administration; DCM: Diabetic cardiomyopathy; STZ: Streptozotocin; HFD: High-fat diet; ΔΨm: Mitochondrial membrane potential; ROS: Reactive oxygen species; HFru: High fructose.

Table 6 Effects of traditional Chinese medicine-derived bioactive compounds on regulating iron metabolism and ferroptosis in diabetic cardiomyopathy

Compounds	Herb source	Drug dosage	Model	Mechanisms
Andrographolide	Green chiretta, Andrographis paniculata (Burm.f.) Wall. ex Nees - Andrographolide	1 mg/kg, 10 mg/kg, 20 mg/kg	STZ-DCM mice; HG-H9c2 cells	Regulates NOX/Nrf2 oxidative stress and NF-κB inflammation/apoptosis[165]
Astragaloside IV	Astragalus, Astragalus membranaceus (Fisch.) Bunge	20 mg/kg/day, 40 mg/kg/day, 80 mg/kg/day (in vivo); 20 μmol/L, 40 μmol/L, 80 μmol/L (in vitro)	STZ-DCM rats, HG-H9c2 cells	↓CD36-mediated lipid uptake; ↓iron overload & lipid peroxidation; ↓ferroptosis markers (ACSL4, PTGS2, MDA); ↑GPX4, SLC7A11; improves cardiac function[166]
Baicalin	Scutellaria baicalensis Georgi (Radix Scutellariae)	100 mg/kg i.g.; 10 LM, 20 LM, and 30 LM in vitro	db/db mice; HG-stimulated cells	Enhances SIRT3 deSUMOylation via SENP1 → restores mitochondrial quality control → inhibits ferroptosis & apoptosis, protects against DCM[160]
Curcumin	Turmeric, Curcuma longa L.	300 mg/kg/day i.g.; 10 μM in vitro	STZ-DCM rabbits; HG/Nor-H9c2 cells	Attenuates ferroptosis via Nrf2/GPX4/HO-1; reduces HG-induced injury[163]
Isoliquiritigenin	Chinese licorice, Glycyrrhiza uralensis Fisch. ex DC.	10 mg/kg, 20 mg/kg i.g. every other day for 12 weeks; 10 μM, 20 μM in vitro	STZ-T1DM mice; HG-H9c2 cells	Enhances Nrf2 activity in high glucose-induced H9c2 cardiomyocyte models[162]
Luteolin	Chinese skullcap, Scutellaria baicalensis Georgi	20 mg/kg i.g. for 15 weeks; 5 and 10 μM in vitro	STZ-DCM mice; HG-H9c2 cells	Enhances Nrf2 activity in high glucose-induced H9c2 cardiomyocyte models[161]
Paeoniflorin	Peony, Paeonia lactiflora Pall.	20 mg/kg/day and 70 mg/kg/day in vivo; 11, 12-EET 1 μM in vitro	STZ-DCM rats; HG-H9c2 cells	Modulates gut microbiota (↑Lactobacillus, Akkermansia; ↑butyrate, indole metabolites); restores NrF2/GPX4 pathway; ↓Fe2+ accumulation, lipid ROS, ACSL4, PTGS2; ↑SLC7A11, GSH; inhibits ferroptosis; improves mitochondrial function and cardiac performance[164]
Schisandrol B	Chinese magnolia vine, Schisandra chinensis (Turcz.) Baill.	12.5 mg/kg, 25 mg/kg (10 weeks)	HFD + STZ-induced diabetic mice, PA-H9C2 cells	Inhibits ferroptosis via p53/SLC7A11/GPX4 axis, improves myocardial lipid metabolism[167]
Sulforaphane	Broccoli (cruciferous vegetables), Brassica oleracea L.	0.5 mg/kg/day (i.p., 12 weeks); 1-5 μM (HG-H9c2 cells)	STZ-DCM mice; HG-H9c2 cells	Regulates ferroptosis via AMPK/Nrf2[124]
Syringaresinol	Clove, Syzygium aromaticum (L.) Merr. & L. M. Perry	Administered i.g. every other day for 8 weeks	STZ-induced type 1 diabetic mice	Alleviates DCM, reduces fibrosis and oxidative stress by downregulating Keap1 and activating Nrf2-NQO1/HO-1[219]

i.p.: Intraperitoneal injection; i.g.: Intragastric administration; DCM: Diabetic cardiomyopathy; STZ: Streptozotocin; HFD: High-fat diet; GSH: Glutathione.

Table 7 Representative combinations of traditional Chinese medicine-derived bioactive compounds with cardioprotective potential in diabetic cardiomyopathy

Compounds	Herb source	Drug dosage	Model	Mechanisms
Artemisinin + Allicin	Sweet wormwood, Artemisia annua L.; Garlic, Allium sativum L.	75 + 40 mg/kg/day i.g., 4 weeks	STZ-induced diabetic rats	Additive inhibition of NF-κB signaling, improved cardiac function and fibrosis[169]
Chlorogenic acid + Ferulic acid	Japanese honeysuckle, Lonicera japonica Thunb.; Chinese angelica, Angelica sinensis (Oliv.) Diels	CGA (110 mg/kg/day and 55 mg/kg/day), and FA (110 mg/kg/day and 55 mg/kg/day) for 15 weeks; 2 μM CGA, 2 μM FA for 24 hours	C57BL/6J mice-DCM model; PA-induced H9c2 cell lipotoxic model	Attenuation of cardiomyocyte lipotoxicity and mitochondrial dysfunction via GCGR-associated metabolic signaling (involving PPARα and AMPK)[170]
Tilianin + Syringin	Moldavian balm, Dracocephalum moldavica L; Ginseng, Panax ginseng C. A. Meyer	Tilianin 60 mg/kg/day (i.p.), Syringin 50 mg/kg/day (i.p.), 8 weeks	STZ + HFD-induced DCM rats; HG-H9c2 cells	Activates PGC-1α/SIRT3 (↑SIRT3, ↑PGC-1α, ↑ATP, ↓ROS, restored ΔΨm); inhibits TLR4/NF-κB/NLRP3 inflammation; reduces apoptosis (↓Bax, cleaved caspase-3; ↑Bcl2)[168]

i.p.: Intraperitoneal injection; i.g.: Intragastric administration; NF-κB: Nuclear factor kappa-B; STZ: Streptozotocin; HFD: High-fat diet; DCM: Diabetic cardiomyopathy; ROS: Reactive oxygen species; ΔΨm: Mitochondrial membrane potential.

Table 8 Application prospects of traditional Chinese medicine formulations in diabetic cardiomyopathy

TCM formulation	Formulation composition	Drug dosage	Model	mechanisms
Ginseng Dingzhi decoction	Ginseng, Panax ginseng C. A. Meyer; Atractylodes macrocephala, Atractylodes macrocephala Koidz.; Poria cocos, Poria cocos (Schw.) Wolf; Chinese yam, Dioscorea opposita Thunb.; Xylooligosaccharides	30 g/kg/day, 15 days	TAC-induced heart failure mice; high-glucose-treated HL-1 cells	Mediated inflammation and cardiomyocyte apoptosis; reduces mitochondrial ROS accumulation and restores redox balance; preserves mitochondrial homeostasis and energy metabolism; promotes TMBIM6-dependent PINK/Parkin-mediated mitophagy and suppresses excessive mitochondrial fission; ultimately attenuates myocardial fibrosis and improves cardiac function after TAC[171]
Fufang Zhenzhu Tiaozhi	Ligustri lucidi fructus, Citri sarcodactylis fructus, Eucommiae cortex, Atractylodis macrocephalae rhizoma, Salviae miltiorrhizae radix et rhizoma, Notoginseng radix et rhizoma, Coptidis rhizome and Cirsii japonici herba et radix	0.6 g/kg/day, 1.2 g/kg/day, and 2.4 g/kg/day, 12 weeks	C57BL/6J diabetic mice	Regulates myocardial lipid metabolism and mitochondrial dynamics (↓CD36, ↓mitochondrial lipid overload; ↓Drp1-mediated fission, ↑mitochondrial fusion; ↑mitochondrial energy metabolism); attenuates lipotoxicity-induced apoptosis (↓Bax, ↓cleaved caspase-3; ↓TUNEL-positive cells)[172]
Taohuajing	Persicae Semen [Prunus persica (L.) Batsch], Polygonatum sibiricum Delar. ex Redouté, and Carthami Flos (Carthamus tinctorius L.)	0.125 g/kg/day, 0.25 g/kg/day, and 0.5 g/kg/day, 12 weeks	C57BL/6 J mice with DCM	Activates SIRT1-mediated antioxidant defense (↑SIRT1, ↑GSH-Px, ↑SOD; ↓ROS, ↓MDA); suppresses NLRP3 inflammasome-driven inflammation (↓NLRP3, ↓pro-inflammatory cytokines); attenuates oxidative stress- and inflammation-induced cardiac dysfunction and fibrosis in DCM
YuNü-Jian	Rehmanniae Radix [Rehmannia glutinosa (Gaertn.) DC.]; Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bunge); Gypsum Fibrosum; Ophiopogonis Radix [Ophiopogon japonicus (L. f.) Ker Gawl.]; Achyranthis Bidentatae Radix (Achyranthes bidentata Blume)	4.52 g/kg/day, 10 weeks	Male SD rats with T2DM	Activates the SIRT1-Nrf2-NQO1 antioxidant axis (↑SIRT1, ↑Nrf2, ↑NQO1, ↑SOD, ↑GSH-Px; ↓ROS, ↓MDA); suppresses NLRP3 inflammasome-mediated inflammation; mitigates oxidative stress-associated cardiac fibrosis and remodeling in diabetes-related cardiomyopathy[174]
Ling-Gui-Zhu-Gan decoction	Poria [Poria cocos (Schw.) Wolf]; Cinnamomi ramulus [Cinnamomum cassia (L.) J. Presl]; Atractylodis Macrocephalae Rhizoma (Atractylodes macrocephala Koidz.); Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch.)	2.1 g/kg/day, 4.2 g/kg/day, and 8.4 g/kg/day, 8 weeks	HFD-induced metabolic cardiomyopathy model-SD rats	r Reduces excessive fatty acid uptake and lipid deposition; Regulates PLIN5-dependent lipid droplet homeostasis; Suppresses lipid peroxidation-driven ferroptosis (↓ACSL4, ↓MDA, ↓lipid peroxidation; ↑GPX4, ↑FPN1, ↑SOD); Preserves mitochondrial structure and function; Attenuates cardiomyocyte injury and cardiac remodeling[175]

TCM: Traditional Chinese medicine; ROS: Reactive oxygen species; DCM: Diabetic cardiomyopathy; GSH: Glutathione; SD: Sprague-Dawley; HFD: High-fat diet.