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.

Key Words: 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.

INTRODUCTION

Diabetic cardiomyopathy (DCM), a chronic myocardial complication of diabetes mellitus independent of coronary artery disease or hypertension, is recognized as a major cause of diabetes-related heart failure. Intensive glycemic control reduces the risk of certain diabetic complications; however, large clinical trials and population-based studies consistently demonstrate that residual cardiovascular risk remains even when HbA1c targets are achieved[1-5]. This persistent cardiovascular vulnerability provides an important clinical context for diabetes-related myocardial complications such as DCM. Epidemiological data suggest that approximately 20%-30% of individuals with diabetes may develop DCM, a condition closely associated with an increased risk of heart failure[6,7]. Globally, an estimated 537 million adults are affected by diabetes, which is projected to rise to 783.2 million by 2045[8]. Reducing the cardiovascular burden of diabetes is an urgent clinical priority[9].

DCM is commonly assessed using imaging modalities such as echocardiography, myocardial radionuclide scanning. However, the asymptomatic or non-specific presentation of early-stage DCM often leads to diagnostic delays. Once overt heart failure develops, prognosis is poor and therapeutic options remain limited. Therefore, early identification and timely intervention are critical but remain challenging[10].

The pathogenesis of DCM is multifaceted. Systemic glucolipotoxicity disrupts myocardial metabolic homeostasis, leading to cardiomyocyte mitochondrial dysfunction and aggravating myocardial injury through multiple pathological processes, including oxidative stress, inflammatory cascades, dysregulated iron storage, and endoplasmic reticulum stress[11,12].

Under diabetic conditions, systemic disturbances in iron metabolism affect multiple organs, including the heart, and iron overload has emerged as a critical mechanism exacerbating myocardial damage. In this context, mitochondria function not only as a primary site of oxidative injury but also as a central hub coordinating iron homeostasis and lipid peroxidation. Although increasing attention has been paid to the roles of mitochondrial dysfunction and ferroptosis in the initiation and progression of DCM, their synergistic interplay and the development of related therapeutic strategies remain insufficiently explored[13,14].

This review focuses on the interplay between mitochondrial dysfunction and ferroptosis in DCM and discusses therapeutic strategies, ranging from standard glucose-lowering agents to novel mechanism-targeted therapies (e.g., iron chelators and mitochondrial protectants) and multi-target approaches such as traditional Chinese medicine (TCM) (Figure 1).

Figure 1 Graphic abstract. Mitochondrial quality control and iron metabolism form a synergistic crosstalk in diabetic cardiomyopathy (DCM). Impaired mitochondrial dynamics, biogenesis, and mitophagy, together with Fe²⁺ overload, oxidative stress, and lipid metabolism imbalance, contribute to ferroptosis, mitochondrial injury, and DCM progression. Current therapeutic strategies include sodium-glucose co-transporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, iron chelators, mitochondrial protectants, and multi-target traditional Chinese medicine. Created with BioRender. DCM: Diabetic cardiomyopathy; SGLT2i: Sodium-glucose co-transporter-2 inhibitors; GLP-1RA: Glucagon-like peptide-1 receptor agonist; ROS: Reactive oxygen species.

FERROPTOSIS AND ITS LINK TO DCM

Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death[15,16]. Ferroptosis is distinct from apoptosis, pyroptosis, and necroptosis in that it is driven by iron-dependent lipid peroxidation. It also exhibits characteristic morphological features, including mitochondrial shrinkage, increased membrane density, and reduced or absent cristae, while lacking the typical chromatin condensation of apoptosis and the prominent cell swelling or membrane rupture associated with necroptosis or pyroptosis[17,18]. Ferroptosis has been implicated in diabetes development, and its cardiovascular complications[19]. Notably, increased labile iron pool (LIP) and elevated expression of ferroptosis-related markers in myocardial tissue from patients with diabetic heart failure suggest the existence of a pro-ferroptotic state in DCM[20].

DCM substantially elevates the risk of heart failure, and glycemic control alone is insufficient to reverse this trajectory. As terminally differentiated cells, cardiomyocytes possess limited regenerative capacity and are highly susceptible to injury. Their loss contributes to irreversible myocardial damage and adverse remodeling, accelerating heart failure progression[21]. Recent studies have identified a novel link between DNA damage response (DDR) and ferroptosis in DCM. Hyperglycemia-induced oxidative stress activates DDR signaling, particularly the DNA-PK complex, which promotes endothelial ferroptosis by enhancing lipid peroxidation and suppressing GPX4-dependent antioxidant defenses. Inhibition of DNA-PK alleviates ferroptosis, improves endothelial function, and restores cardiac performance, highlighting the DDR-ferroptosis axis as a key pathogenic mechanism in DCM. These findings suggest that ferroptosis may represent a convergence point of metabolic, oxidative, and genomic stress in DCM[22].

Reactive oxygen species generation - an initiating event of ferroptosis

Mitochondria are the primary intracellular source of reactive oxygen species (ROS). In DCM, ferroptosis-associated iron-sulfur cluster deficiency promotes increased electron leakage from mitochondrial respiratory chain complexes I/III and enhances reverse electron transport, thereby driving excessive mitochondrial ROS production. This process is dependent on mitochondrial-localized PARP1[23].

At the clinical level, liquid chromatography-tandem mass spectrometry (LC-MS/MS-based) proteomic analysis of myocardial tissue from patients with diabetic heart failure has identified multiple key proteins implicated in diabetes-induced cardiac ferroptosis. Notably, cytochrome b-245 heavy chain (CYBB), a core subunit of NADPH oxidase (NOX), is upregulated, indicating marked activation of ROS-generating pathways. Concurrently, the expression of voltage-dependent anion-selective channel protein 2, which is essential for maintaining mitochondrial membrane potential (ΔΨm) homeostasis, is downregulated, further supporting the presence of ΔΨm dysfunction in the hearts of diabetic patients[20].

In parallel, NOX activation under hyperglycemia and hyperlipidemia further amplifies ROS driving lipid peroxidation and pro-inflammatory signaling such as nuclear factor kappa-B (NF-κB) and MAPK, which promote myocardial fibrosis and remodeling[24,25].

Lipid peroxidation - defining features of ferroptosis

Lipid peroxidation is a defining feature of ferroptosis. Accumulating experimental evidence indicates that abnormal lipid accumulation within cardiomyocytes represents a key pathological characteristic of DCM. For example, TGR5-deficient mice subjected to a high-fat diet (HFD)/streptozotocin (STZ) regimen, as well as db/db mice, exhibit pronounced accumulation of free fatty acids (FFAs), triglycerides, and diacylglycerols in myocardial tissue[26]. This excessive lipid burden provides an abundant substrate pool for lipid peroxidation.

Under chronic hyperglycemic and lipotoxic conditions, cardiomyocytes undergo metabolic reprogramming, shifting from predominantly glucose oxidation toward fatty acid β-oxidation. Within this metabolic context, polyunsaturated fatty acids (PUFAs) are preferentially incorporated into phosphatidylethanolamines, generating PUFA-enriched membrane phospholipids that markedly increase cellular susceptibility to ferroptosis[27]. These PUFA-containing phospholipids readily react with free radicals to form lipid peroxyl radicals, thereby triggering chain reactions and leading to the accumulation of toxic lipid peroxidation products[28].

Consistent with these mechanistic insights, myocardial tissue from patients with diabetic heart failure shows significantly elevated levels of the lipid peroxidation marker 4-hydroxynonenal and its protein adducts, providing direct clinical evidence for enhanced lipid peroxidation in diabetes-associated human heart failure and supporting its relevance to DCM[20].

Iron overload - essential catalytic driver of ferroptosis

Iron overload is widely recognized as a central driver of ferroptosis. Growing evidence indicates that type 2 diabetes mellitus (T2DM) is frequently associated with dysregulated iron metabolism, manifested by elevated serum iron and ferritin levels together with aberrant hepcidin regulation[29-31], thereby placing the organism in a systemic milieu prone to iron dysregulation and iron overload. At the organ level, cardiac magnetic resonance imaging studies in patients with severe diabetic heart failure have identified abnormal myocardial iron accumulation that is associated with lipotoxicity and cardiac dysfunction[32]. Mechanistic insights into this process were provided by Fang et al[33] in Circulation Research, who demonstrated through cardiomyocyte-specific ferritin heavy chain (ferritin H) deficiency and dietary iron overload models that disruption of cardiac iron homeostasis markedly enhances ferroptosis and precipitates cardiomyopathy.

Furthermore, Gawargi et al[20] reported that, based on coordinated alterations in iron-handling proteins and functional evidence of ferroptosis, the LIP is functionally expanded in diabetic myocardium. This expansion is likely attributable to multiple converging mechanisms, including enhanced heme degradation, increased DMT1-mediated iron uptake, diminished ferritin-based iron sequestration, and impaired iron export via FPN1[20]. Collectively, these alterations establish a highly reactive iron milieu within the diabetic heart, thereby facilitating ferroptosis-driven myocardial injury.

Oxidative stress - permissive environment of ferroptosis

Oxidative stress is a permissive environment of ferroptosis in DCM. Normally, the cystine/glutamate antiporter (System Xc^-)/glutathione (GSH)/GPX4 axis detoxifies lipid peroxides and maintains redox balance, but in myocardial tissues from diabetic heart failure patients, GPX4 expression and activity are reduced, along with downregulation of ATF4 and Nrf2, indicating impaired antioxidant defenses and ferroptosis activation[20,21]. Consistently, animal studies show that levels of the antioxidant molecule GSH, as well as antioxidant enzymes such as SOD1 and NQO1 are markedly decreased, further aggravating lipid peroxidation and ROS-induced injury[34,35].

In addition to the classical GPX4-dependent mechanism, the recently identified ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 (CoQ10)-NAD(P)H axis has emerged as a GPX4-independent antioxidant defense pathway that mitigates ferroptosis[36,37]. By regenerating reduced CoQ10 in an NAD(P)H-dependent manner, this axis directly terminates lipid peroxidation chain reactions, thereby restraining the execution of ferroptosis.

Under conditions of impaired glucose metabolism, altered NADPH homeostasis may constrain FSP1 activity and weaken CoQ10-mediated antioxidant capacity, thereby creating a permissive environment for lipid peroxidation amplification and ferroptosis initiation[19,38].

MITOCHONDRIAL HOMEOSTASIS DISRUPTION AND ITS LINK TO DCM

The heart depends critically on mitochondrial ATP production; accordingly, disruption of myocardial energy metabolism is now recognized as a central pathogenic mechanism in DCM[39].

Since the initial report of impaired mitochondrial respiration in diabetic mice in 1985, mitochondrial dysfunction has been consistently documented across various diabetic models, accumulating evidence indicates that in type 1 diabetes mellitus (T1DM)-like models (Akita mice), mitochondrial injury is characterized by ultrastructural abnormalities, while mitochondria remain largely coupled despite increased uncoupling protein 3 expression[40]. In contrast, T2DM-like models (db/db and ob/ob mice) and diet-induced obesity models exhibit more pronounced mitochondrial dysfunction driven by fatty acid substrate overload, characterized by mitochondrial uncoupling and diminished energetic efficiency (reflected by a reduced ADP/O ratio)[39,41]. Wang et al[42] examined cardiac mitochondrial ultrastructure in a T2DM-like DCM mouse model induced by STZ combined with a HFD, using scanning electron microscopy followed by three-dimensional visualization and reconstruction analysis. Their analysis revealed marked mitochondrial abnormalities, including cristae dissolution, disordered organization, and vacuolization within the cristae, along with the presence of abnormally enlarged mitochondria (mega-mitochondria), providing morphological evidence for profound disruption of mitochondrial structure and function in DCM[42]. Collectively, these studies indicate profound disruption of mitochondrial homeostasis, characterized by abnormalities in mitochondrial morphology and function, during the progression of DCM.

Clinical studies further support this association. Diamant et al[43] used echocardiography to detect impaired diastolic function in asymptomatic diabetic patients without hypertension. ³¹P-magnetic resonance spectroscopy revealed significantly reduced phosphocreatine-to-ATP ratios in the diabetic group, suggesting mitochondrial energy deficiency as an early contributor to cardiac dysfunction. Anderson et al[44] reported increased mitochondrial sensitivity to calcium-induced mitochondrial permeability transition pore (mPTP) opening and elevated H₂O₂ production in cardiomyocytes from diabetic patients, providing clinical evidence for mitochondria-dependent cell death in diabetes. Similarly, Croston et al[45] isolated mitochondrial subpopulations from the atrial appendages of T2DM patients and found impaired respiration in subsarcolemmal mitochondria, along with reduced activity and expression of electron transport chain (ETC) complexes I and IV.

In DCM, mitochondrial dysfunction is characterized by a reduction in mitochondrial number, ultrastructural abnormalities, impaired activity of multienzyme complexes, and decreased ATP synthesis. These defects are mechanistically driven by hyperglycemia-induced calcium overload, excessive ROS generation, and aberrant mPTP opening[46]. Moreover, persistent hyperglycemia promotes the formation of advanced glycation end-products (AGEs), which, in concert with insulin resistance and oxidative stress, further disrupt the respiratory chain and suppress ATP production. Together, these processes activate multiple cell injury pathways, ultimately leading to cardiomyocyte apoptosis or necrosis[47]. The imbalance of lipid metabolism induced by diabetes leads to lipotoxicity, which disrupts mitochondrial homeostasis and generates excessive mitochondrial ROS. This, in turn, results in oxidative damage to mtDNA and its release into the cytoplasm. Simultaneously, it activates the cGAS-STING-mediated pyroptosis pathway in cardiomyocytes, exacerbating the progression of DCM[48].

Beyond energy production, mitochondria play a critical role in maintaining cardiac iron homeostasis. These functions are governed by mitochondrial quality control (MQC), an integrated system encompassing mitochondrial dynamics (fusion and fission), mitophagy, and biogenesis[49,50].

Mitochondrial dynamics in DCM

Live-cell imaging demonstrates that mitochondria are highly dynamic organelles, undergoing continuous fusion and fission to preserve network integrity and function[51,52].

Mitochondrial fusion is primarily mediated by the dynamin-related GTPases mitofusin-1 and mitofusin-2 (MFN1/2) on the outer mitochondrial membrane and optic atrophy 1 (OPA1) on the inner mitochondrial membrane. By facilitating the exchange of mitochondrial DNA, proteins, and metabolites, fusion supports mitochondrial functional integrity and bioenergetic efficiency. Mitochondrial fission is mainly regulated by dynamin-related protein 1 (Drp1), which is recruited to the outer mitochondrial membrane via adaptor proteins such as Mff, MiD49/51, and Fis1, contributing to MQC[53,54].

Accumulating evidence indicates that impaired mitochondrial dynamics contribute significantly to the pathogenesis of DCM. Montaigne et al[55] reported that myocardial contractile dysfunction in patients with T2DM - but not in metabolically healthy obese individuals - is associated with mitochondrial network fragmentation and decreased MFN1 expression in cardiac tissue. Clinical observations further suggest that offspring born to mothers with diabetes or obesity exhibit increased susceptibility to cardiovascular disease. Using live-cell confocal imaging, Larsen et al[56] demonstrated that maternal diabetes and HFD disrupt mitochondrial dynamics in neonatal rat cardiomyocytes.

Experimental studies indicate that hyperglycemia and lipotoxicity activate Drp1 by increasing Ser616 and reducing Ser637 phosphorylation, thereby promoting excessive mitochondrial fission. In high glucose-treated primary neonatal rat cardiomyocytes, Drp1 and Fis1 are upregulated, whereas MFN1 and MFN2 are downregulated and undergo increased ubiquitination; these alterations are accompanied by reduced ΔΨm, enhanced mPTP opening, and ATP depletion[57]. In lipotoxic models, including cardiomyocyte-specific ACSL1-overexpressing mouse hearts and palmitate-treated neonatal rat ventricular cardiomyocytes, lipid overload increases mitochondrial ROS and promotes mitochondrial fission through AKAP121 ubiquitination, reduced Drp1 Ser637 phosphorylation, and impaired OPA1 processing[58]. Importantly, excessive mitochondrial ROS generated by Drp1-driven mitochondrial fragmentation provides a direct source of oxidative stress that accelerates lipid peroxidation of polyunsaturated fatty acid-containing phospholipids, thereby lowering the threshold for ferroptotic cell death.

In early stages of T1DM in mouse models (week 3), mitochondrial structure and function appear relatively preserved. However, by week 5, a marked increase in H₂O₂ production and accumulation of vacuolated mitochondria occurs. These changes coincide with decreased levels of long-form OPA1 and increased short-form OPA1, reflecting enhanced fission and diminished fusion capacity[59]. Importantly, early pharmacological inhibition of mitochondrial fission has been shown to attenuate ROS production and mitochondrial fragmentation, underscoring the therapeutic potential of targeting mitochondrial dynamics in DCM[60].

Mitophagy in DCM

Autophagy is a conserved intracellular degradation system that delivers cytoplasmic components, including proteins and organelles, to lysosomes for degradation and recycling, whereas mitophagy is a specialized form of autophagy that mediates the selective clearance of mitochondria. Beyond mitophagy, autophagy may also regulate ferroptosis through broader pathways involved in iron homeostasis and redox balance[61]. In particular, NCOA4-mediated ferritinophagy promotes ferritin degradation, increases the LIP, and facilitates lipid peroxidation, thereby sensitizing cells to ferroptosis. Emerging evidence in diabetic and cardiovascular settings suggests that excessive autophagy may aggravate ferroptosis by enhancing ferritinophagy and free iron accumulation, whereas suppression of this pathway may alleviate oxidative injury and improve cardiac function. Therefore, the crosstalk between autophagy and ferroptosis in DCM is not limited to MQC, but also involves ferritin turnover, intracellular iron mobilization, and antioxidant imbalance[62].

Mitophagy is a selective form of autophagy that is commonly initiated by loss of ΔΨm, in which damaged or excess mitochondria are eliminated through lysosomal degradation[63]. This process is primarily regulated by two distinct mechanisms: A ubiquitin-dependent pathway and a receptor-mediated, ubiquitin-independent pathway. In the ubiquitin-dependent pathway, mitophagy is mediated by the PINK1/Parkin axis. Upon mitochondrial depolarization, PINK1 accumulates on the outer mitochondrial membrane and recruits Parkin, which ubiquitinates outer membrane proteins such as VDAC1 and MFN1/2. These ubiquitin signals are recognized by adaptor proteins, including p62, OPTN, and NDP52, which interact with LC3 to promote mitophagosome formation and subsequent lysosomal degradation[64,65].

The ubiquitin-independent pathway involves outer membrane receptors such as BNIP3 and FUNDC1. Under stress conditions like hypoxia, these receptors enhance LC3 binding through phosphorylation of their LIR motifs, thereby initiating mitophagy[66-70]. In addition, lipids such as cardiolipin and ceramide can directly interact with LC3 to mediate receptor-independent mitophagy[71].

Hyperglycemia and lipotoxicity contribute to mitophagic imbalance in DCM. During the early stages of myocardial injury, mitophagy serves a protective role by removing damaged mitochondria and reducing oxidative stress. However, excessive mitophagy may lead to mitochondrial depletion, while insufficient mitophagy results in the accumulation of dysfunctional mitochondria - both contributing to disease progression[72].

Notably, mitophagy appears to differs between T1DM and T2DM in timing, intensity, and pathological impact. In terms of timing, In HFD-induced T2DM models, mitophagy is activated as early as three weeks and remains elevated for at least two months, whereas bulk autophagy peaks later, around six weeks, highlighting a temporal dissociation and suggesting that early mitophagy serves as a compensatory response to chronic lipotoxic stress[73]. In contrast, in STZ-induced T1DM models, autophagic flux becomes progressively impaired; although early responses may be maintained, a pronounced decline emerges after approximately six months, indicating a transition from adequate flux to blockade[74]. In T1DM models, prolonged high-glucose exposure leads to impaired mitophagic flux, as evidenced by disrupted mitochondrial cristae structure and diminished clearance[75]. In intensity, T2DM is marked by an early and sustained increase in mitophagy, characterized by enhanced sequestration of mitochondria into LC3-positive autophagosomes, whereas bulk autophagy follows a delayed trajectory[73]. In contrast, in T1DM, despite increases in autophagosomes and lysosomes, defective maturation of autolysosomes results in insufficient flux - a pattern historically associated with bulk autophagy and mechanistically distinct from the selective, early mitophagy observed in T2DM[76].

Pathologically, hyperglycemia-induced lysosomal dysfunction in T1DM - including reduced acidity and cytosolic leakage of cathepsin D - promotes cardiomyocyte apoptosis. Restoration of mitophagy through Parkin overexpression mitigates high-glucose-induced injury[77]. In T2DM, inhibition of mitophagy exacerbates mitochondrial dysfunction, lipid accumulation, and diastolic impairment, whereas pharmacological activation with TAT-Beclin1 alleviates mitochondrial dysfunction and improves cardiac performance, underscoring mitophagy as a promising therapeutic target in DCM[73].

Clinical evidence implicates dysregulated mitophagy in the progression of DCM. In right atrial appendage tissue from patients undergoing coronary artery bypass grafting, Munasinghe et al[78] observed elevated LC3B-II and Beclin-1 expression by western blot, together with increased autophagosome formation and reduced p62 levels in diabetic patients, indicative of enhanced autophagic flux. These observations highlight mitophagy as a distinct and targetable mechanism for therapeutic intervention in DCM.

Mitochondrial biogenesis in DCM

Mitochondrial biogenesis is a fundamental process that preserves mitochondrial abundance and functional integrity[79], encompassing mitochondrial membrane formation, protein import, and mtDNA replication, with PGC-1α serving as the central regulatory hub[80].

In response to increased energetic demand, activation of the AMPK-SIRT1 axis induces phosphorylation and deacetylation of PGC-1α, thereby enhancing oxidative phosphorylation and the expression of genes involved in mitochondrial oxidative metabolism[81-84]. Activated PGC-1α subsequently cooperates with NRF-1 and NRF-2 to induce TFAM transcription, which drives mtDNA replication and transcription and ultimately promotes mitochondrial biogenesis[85]. Moreover, PGC-1α exerts cardioprotective effects by regulating PPARα/δ signaling to augment fatty acid oxidation and attenuating oxidative stress[86]. In addition to PGC-1α-dependent mechanisms, c-Myc has also been shown to modulate mitochondrial biogenesis via the NRF-1-TFAM axis, contributing to improved cardiac function[87,88].

PGC-1α transcription is epigenetically and transcriptionally suppressed, as evidenced by promoter hypermethylation, proteomic downregulation of mitochondrial respiratory and fatty acid oxidation proteins, and reduced PGC-1α mRNA expression in cardiac tissue and circulation, collectively indicating impaired mitochondrial biogenesis in DCM[80,89-91].

MicroRNA-mediated regulation further contributes to this process. Reduced plasma miR-144 levels in diabetic patients with cardiac dysfunction have been shown to impair Rac1-AMPK-SIRT1 signaling, whereas miR-144 overexpression enhances PGC-1α deacetylation, promotes mitochondrial biogenesis, and confers cardioprotection under hyperglycemic conditions[93].

Consistently, in vivo DCM models exhibit impaired mitochondrial biogenesis, accompanied by reduced mtDNA replication and transcription and inhibited PGC-1α/Akt signaling[92]. While systemic or cardiac-specific deletion of PGC-1α/β results in defective mitochondrial biogenesis during late fetal development and lethal heart failure, underscoring the indispensable role of PGC-1 coactivators in cardiac mitochondrial maturation[94].

The sirtuin family represents another critical regulatory layer. Cardiac SIRT1 or SIRT3 deficiency disrupts mitochondrial biogenesis and abolishes therapeutic benefits in DCM models, whereas SIRT6 activation restores AMPK/PGC-1α/Akt signaling and ameliorates disease progression[95-97].

Additional regulators, including Caveolin-3, further modulate mitochondrial biogenesis through Akt-dependent pathways, supporting mitochondrial biogenesis as a potential therapeutic target in DCM[98].

THE INTERACTION BETWEEN FERROPTOSIS AND MITOCHONDRIAL DAMAGE IN DCM

Mitochondria represent a central intracellular hub for iron metabolism and energy conversion. By coordinating iron uptake, utilization, and storage, they maintain mitochondrial iron homeostasis. Moreover, through the efficiency of Fe-S cluster biosynthesis and the regulation of mitochondrial iron export, mitochondria modulate the cytosolic LIP, thereby indirectly contributing to overall cellular iron homeostasis[99-101]. A schematic overview of these mechanisms is provided in Figure 2.

Figure 2 Iron homeostasis and mitochondrial iron metabolism in cardiomyocytes Schematic representation of iron uptake, intracellular transport, storage, and mitochondrial utilization in cardiomyocytes. Upon entering the mitochondrial matrix, iron can be channeled to three pathways: Heme biosynthesis, iron-sulfur (Fe-S) cluster biogenesis, or storage in mitochondrial ferritin (FtMt). Cytosolic Fe²⁺ comprises the labile iron pool, which is either stored in ferritin or exported via ferroportin, whose activity is negatively regulated by hepcidin. Upon entering the mitochondrial matrix, iron can be channeled to three pathways: Heme biosynthesis, iron-sulfur (Fe-S) cluster biogenesis, or storage in FtMt. ABCB7 and ABCB8 mediate Fe-S cluster export and mitochondrial iron efflux, respectively. Created with BioRender. Fe-S: Iron-sulfur; FtMt: Mitochondrial ferritin; LIP: Labile iron pool.

In diabetic cardiomyocytes, disruption of iron homeostasis together with impaired Fe-S cluster biosynthesis compromises mitochondrial ETC function and induces oxidative stress, ultimately increasing susceptibility to ferroptosis[23,101].

In turn, ferroptosis-associated lipid peroxidation and iron-dependent oxidative injury further exacerbate mitochondrial ROS generation and accelerate mitochondrial functional decline, creating a vicious cycle in which mitochondrial dysfunction and ferroptosis mutually reinforce one another. Consistent with these molecular events, ferroptosis is characteristically accompanied by distinct mitochondrial morphological alterations, including reduced mitochondrial size, increased membrane density, and loss of cristae architecture[16].

Importantly, dihydroorotate dehydrogenase (DHODH) - a flavin-dependent enzyme embedded in the inner mitochondrial membrane - has emerged as a key modulator of mitochondrial ferroptosis. By reducing ubiquinone to ubiquinol, DHODH limits lipid peroxidation and delays ferroptosis progression[102]. This highlights a mechanistic bridge between mitochondrial redox metabolism and ferroptotic regulation. Wang et al[23] demonstrated that loss of NFS1 persulfidation at Cys383 disrupts Fe-S cluster biosynthesis, impairs ETC activity, and induces excessive ROS accumulation, DNA oxidation, and PARP1 overactivation in DCM. Collectively, these events culminate in PARthanatos, a distinct form of programmed cell death tightly linked to mitochondrial dysfunction. Together, these findings highlight the intimate interplay between iron metabolism and mitochondrial dysfunction.

Mitochondrial dynamics and ferroptosis

Khamseekaew et al[103] demonstrated that chronic iron exposure increased the Drp1/Mfn2 ratio in the hearts of both wild-type, thereby inducing mitochondrial fragmentation and consequent cardiac dysfunction. These findings indicate that iron overload can directly disrupt mitochondrial dynamics homeostasis in cardiomyocytes[103]. Consistently, in animal and cellular models of DCM, a pronounced shift toward mitochondrial fission - characterized by DRP1 upregulation and MFN2 downregulation - has been observed. Transmission electron microscopy further revealed extensive mitochondrial fragmentation accompanied by enhanced lipid peroxidation and elevated ROS levels, indicating the coexistence of mitochondrial dynamics imbalance and ferroptosis-related phenotypes in DCM. Notably, inhibition of PACS2 simultaneously ameliorated mitochondrial dynamics abnormalities and ferroptosis-associated alterations, implicating the PACS2/CPT1A/DHODH signaling axis as a potential regulatory node that modulates mitochondrial metabolism and redox balance, thereby indirectly maintaining mitochondrial structural integrity and contributing to the development and progression of ferroptosis in DCM[104].

Mitophagy and its relationship with ferroptosis

In the early stage of iron overload, mitochondria can transiently sequester excess iron, thereby serving as a buffering system. Under this condition, mitophagy functions as an adaptive protective response, mitophagy helps alleviate iron-induced ROS production by selectively degrading damaged, iron-loaded mitochondria[105].

As iron burden and mitochondrial stress evolve, the activation of mitophagy becomes context-dependent. Iron chelation has been shown to attenuate PINK1/Parkin-mediated mitophagy by reducing mitochondrial iron burden and injury signals,and reduce Drp1 phosphorylation, thereby restoring mitochondrial integrity. In Fe³⁺-overloaded H9C2 cardiomyocytes, knockdown of lipocalin-2 or its receptor significantly suppresses iron uptake, fission, and autophagy/mitophagy-related markers (e.g., LC3-II), while alleviating apoptosis[106].

Mitochondrial biogenesis and its relationship with ferroptosis

In T2DM mouse and cardiomyocyte models, LGR6 deletion worsens cardiac dysfunction, while LGR6 overexpression attenuates ferroptosis and promotes biogenesis via the STAT3/PGC-1α pathway[107]. Similarly, in vitro experiments show that Nr2f2 knockdown suppresses ferroptosis and improves mitochondrial function by upregulating PGC-1α; however, the protective effect is abrogated by PGC-1α knockdown[108].

The integrative crosstalk between mitochondrial dysfunction and ferroptosis in DCM is summarized in Figure 3.

Figure 3 Crosstalk between mitochondrial dysfunction and ferroptosis in the pathogenesis of diabetic cardiomyopathy. This schematic depicts the interplay between mitochondrial quality control and iron metabolism in diabetic cardiomyopathy (DCM). Hyperglycemia and elevated free fatty acids impair mitochondrial cristae integrity and enhance reactive oxygen species generation, whereas excessive iron uptake and dysregulated storage cause iron overload and expansion of the labile iron pool. These alterations promote lipid peroxidation via ACSL4/LOX pathways and disrupt redox homeostasis, thereby linking mitochondrial dysfunction with ferroptosis. Antioxidant defense mechanisms - including System Xc^-, glutathione, GPX4, and Nrf2 - counteract ferroptotic stress. The synergistic interaction between mitochondrial impairment and ferroptosis drives cardiomyocyte hypertrophy, myocardial fibrosis, and adverse cardiac remodeling, ultimately accelerating the progression of DCM. FFAs: Free fatty acids; ETC: Electron transport chain; NOX: NADPH oxidase; DCM: Diabetic cardiomyopathy; ROS: Reactive oxygen species; GSH: Glutathione.

CURRENT TREATMENTS FOR DCM: CHALLENGES AND ADVANCES IN FERROPTOSIS AND MITOCHONDRIAL DYSFUNCTION

Despite advances in diabetes management, current therapeutic approaches for DCM remain largely limited to metabolic control and symptomatic treatment of heart failure[109]. Early-stage DCM is often asymptomatic and difficult to diagnose, and disease-specific targeted therapies are still lacking[109]. Increasing evidence has identified mitochondrial dysfunction and ferroptosis as key contributors to DCM pathogenesis, prompting growing interest in related therapeutic interventions[110].

Standard glucose-lowering agents

Sodium-glucose co-transporter-2 inhibitors: Sodium-glucose co-transporter-2 (SGLT2) inhibitors lower blood glucose by blocking renal glucose reabsorption andhave attracted growing interest for their cardioprotective potential in DCM. In DCM models, empagliflozin improved cardiac function, upregulated GPX4 expression, and reduced cardiomyocyte ferroptosis by stabilizing NRF2 through the USP7/NRF2/GPX4 signaling pathway[111]. These protective effects were mechanistically associated with enhanced Nrf2-mediated GSH synthesis, indicating restoration of endogenous antioxidant defenses. Furthermore, in STZ combined with HFD-induced diabetic mouse models, canagliflozin reduced myocardial accumulation of both total and ferrous iron, thereby restoring cardiac iron homeostasis. This effect was accompanied by activation of the system Xc^-/GSH/GPX4 axis, ultimately leading to inhibition of ferroptosis[112].

Complementing these in vivo findings, in vitro studies using cardiomyocyte cell lines have provided further mechanistic insights into the cardioprotective actions of SGLT2 inhibitors.

In an HL-1 cell model of DCM, canagliflozin attenuated myocardial lipotoxicity by activating the AMPK signaling pathway, thereby modulating inflammation and ferroptosis[113].

In addition, cellular studies demonstrated that canagliflozin enhances PINK1-Parkin-dependent mitophagy, resulting in improved MQC and restoration of mitochondrial function under diabetic conditions[114].

Although SGLT2 inhibitors exhibit cardioprotective potential in DCM, their clinical application remains limited by safety concerns, including genitourinary infections, euglycemic diabetic ketoacidosis, and signals of increased fracture and amputation risk reported in selected studies[115,116].

Dipeptidyl peptidase-4 inhibitors: Beyond their glucose-lowering effects, dipeptidyl peptidase-4 (DPP-4) inhibitors exert cardioprotective actions in DCM, partly by modulating MQC. Pham et al[117] reported that the DPP-4 inhibitor evogliptin enhanced both systolic and diastolic cardiac function in db/db mice, reduced myocardial hypertrophy and fibrosis, mitigated cardiac lipotoxicity, and restored mitochondrial integrity. These protective effects appear to be mediated via activation of the PGC-1α/NRF1/TFAM signaling pathway, thereby promoting mitochondrial biogenesis[117].

However, the clinical use of DPP-4 inhibitors warrants careful evaluation of their safety profile. Concerns have been raised regarding a potential risk of heart failure associated with certain DPP-4 inhibitors, underscoring the importance of individualized risk-benefit assessment in patients with DCM[118].

Glucagon-like peptide-1 receptor agonists: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve cardiac structure, reduce myocardial hypertrophy and fibrosis, attenuate inflammation and oxidative stress, and enhance overall cardiac performance[119].

Liraglutide has been shown to mitigate myocardial ferroptosis through activation of the Nrf2/GPX4 signaling pathway, thereby exerting cardioprotective effects in DCM[120]. Notably, clinical observational studies have reported that patients with T2DM and concomitant hereditary hemochromatosis receiving GLP-1RA therapy exhibited lower serum ferritin levels[121].

Novel mechanism-targeted therapies

Iron chelators and other ferroptosis inhibitors: Fer-1 and liproxstatin-1 (Lip-1) are widely recognized as prototypical ferroptosis inhibitors. Acting as radical-trapping antioxidants, they suppress ferroptosis primarily by preventing lipid peroxidation within membrane phospholipids and by modulating the Nrf2/ARE antioxidant pathway along with related signaling cascades[122-125].

Iron chelators, such as deferoxamine and deferasirox, can alleviate iron overload by reducing levels of labile iron. However, their clinical applications are limited by adverse effects, including nephrotoxicity and immune dysfunction[126,127]. In contrast, next-generation chelators such as CN128[128] and ciclopirox[129] demonstrate enhanced safety profiles together with strong iron-chelating and antioxidant activities, thereby providing cardiomyocyte protection.

Mitochondrial protectants - mitophagy inducers: Accumulating evidence indicates that melatonin enhances mitophagy by promoting Parkin translocation to mitochondria and upregulating LC3-II expression[130]. Alisporivir induces mitophagy through increased transcription of PINK1 and Parkin, thereby reducing mitochondrial lipid peroxidation and offering myocardial protection in diabetic models[131].

Antioxidants and mitochondrial ROS scavengers: Excessive mitochondrial ROS accumulation is a key driver of diabetes-related mitochondrial injury. The mitochondrial ROS scavenger mito-TEMPO reduces oxidative stress, prevents cardiomyocyte apoptosis, and ameliorates cardiac hypertrophy in both T1DM and T2DM mouse models[132]. In parallel, other mitochondria-targeted antioxidant strategies - including CoQ10, FSP1, and lipid ROS inhibitors - have been shown to preserve mitochondrial functional homeostasis by inhibiting ferroptosis and lipid peroxidation, thereby mitigating oxidative damage[133,134].

Other intervention strategies targeting mitochondrial dysfunction: Methylglyoxal (MGO), a glycolysis byproduct and precursor of AGEs, contributes to mitochondrial dysfunction. MGO scavengers such as MitoGamide have demonstrated cardioprotective effects, including improved diastolic function in Akita diabetic mice[135,136].

Collectively, these findings indicate that both standard glucose-lowering agents and emerging mechanism-targeted therapies exert cardioprotective effects in DCM or diabetes-associated cardiac injury, as summarized in Table 1.

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.

THE USE OF TCM FOR DCM BY FOCUSING ON FERROPTOSIS AND MITOCHONDRIAL HOMEOSTASIS DISRUPTION

Rooted in a holistic framework and backed by over 2000 years of clinical practice, TCM is increasingly recognized as a promising adjunct or alternative therapeutic approach. Notably, many TCM-derived bioactive compounds are well-tolerated, widely accessible, and exert therapeutic effects via multi-target, multi-pathway mechanisms. Given the multifactorial and interconnected nature of DCM pathogenesis, single-target pharmacological strategies often prove inadequate. In contrast, the pleiotropic regulatory capacity of TCM is gaining attention, with growing evidence elucidating its molecular basis of action[137,138].

Resveratrol, a polyphenolic compound derived from Japanese knotweed (Reynoutria japonica Houtt.), has been extensively investigated for its cardioprotective effects in DCM. Experimental evidence indicates that resveratrol activates the SIRT1-PGC-1α signaling axis, thereby enhancing mitochondrial biogenesis and function, while simultaneously exerting anti-ferroptotic effects via the Nrf2-GPX4 pathway[95,139].

Furthermore, resveratrol provides anti-ferroptotic protection via the Nrf2-GPX4 pathway. In STZ-induced T1DM-DCM mice, resveratrol treatment alleviated iron overload and lipid peroxidation, improved cardiac function, and preserved mitochondrial ultrastructural integrity[140,141].

These promising preclinical findings have prompted clinical evaluation[142-144]. A systematic review encompassing 15 randomized controlled trials with 896 participants reported significant improvements in insulin resistance, glycemic control, and oxidative stress in patients receiving resveratrol supplementation[145].

Salidroside, a bioactive compound derived from Rhodiola rosea L., has been consistently reported to exert cardioprotective effects in DCM. In diabetic mice, salidroside inhibited ferroptosis and improved myocardial ultrastructure through regulation of iron homeostasis and autophagy-related pathways[146]. In parallel, salidroside activated the AMPK/Akt-SIRT3 signaling axis, upregulated PGC-1α and TFAM expression, and thereby promoted mitochondrial biogenesis, restored mitochondrial function, and enhanced myocardial energy metabolism[147].

Collectively, these data underscore the multi-target therapeutic potential of TCM-derived bioactive compounds, a growing number of TCM-derived bioactive compounds have shown modulatory effects on iron metabolism, mitochondrial dynamics, mitophagy, and biogenesis - offering valuable adjunctive strategies for DCM (Tables 2, 3, 4, 5, and 6). Botanical nomenclature has been standardized according to World Flora Online (www.worldfloraonline.org) and The Plant List (www.theplantlist.org).

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.

Regulation of mitochondrial dynamics by TCM

In DCM, mitochondrial fusion-fission dynamics have emerged as potential regulatory targets of TCM-derived bioactive compounds (Table 3).

Representative TCM-derived bioactive compounds, including Ginsenoside Rb1 (from Panax ginseng), Ophiopogonin (from Ophiopogon japonicus), Paeonol (from Cortex Moutan), Perillaldehyde (from Perilla frutescens), Punicalagin (from Pomegranate, Punica granatum L.), Rhein (from Rheum palmatum), do not exert their effects through uniform regulation of all fusion and fission-related proteins. Instead, these agents target distinct key nodes within mitochondrial fusion or fission pathways, thereby collectively re-establishing the fusion-fission balance.

Specifically, certain TCM-derived bioactive compounds primarily enhance mitochondrial fusion by upregulating MFN1/2 or OPA1, whereas others predominantly attenuate excessive mitochondrial fission by inhibiting Drp1 or p-Drp1^S616 signaling. Although their upstream regulatory mechanisms differ - ranging from activation of the CK2α-Stat3 axis (Paeonol), miRNA-dependent regulation and GSK-3β inhibition (Perillaldehyde), to direct modulation of the core fusion-fission machinery (Rhein) - their downstream functional outcomes converge remarkably. At the integrated level, these interventions consistently restore mitochondrial dynamic homeostasis, thereby alleviating oxidative stress, apoptosis, and lipotoxic injury, and ultimately suppressing pathological cardiac remodeling. Notably, these protective effects have been repeatedly validated in both in vivo and in vitro models of DCM[148-153].

Regulation of mitophagy by TCM

In DCM, mitophagy has emerged as a potential regulatory target of TCM-derived bioactive compounds (Table 4).

For instance, Fucoxanthin (from Undaria pinnatifida) has been shown to alleviate oxidative stress, restore mitophagy, thereby ameliorating myocardial structural injury under diabetic conditions[154].

Heterophyllin B (from Pseudostellaria heterophylla) is more closely associated with the maintenance of mitochondrial homeostasis; through MAVS-related signaling, it modulates mitophagy and autophagic flux while concomitantly promoting mitochondrial fusion and reducing mitochondrial ROS accumulation, thereby preserving mitochondrial functional integrity[155].

In comparison, studies on Tanshinone IIA (from Salvia miltiorrhiza) have primarily focused on the canonical PINK1-Parkin-dependent mitophagy pathway, indicating that its coordinated regulation of autophagy-related protein expression contributes to the restoration of mitochondrial ultrastructure[156].

Regulation of mitochondrial biogenesis by TCM

In DCM, mitochondrial biogenesis has emerged as potential regulatory targets of TCM-derived bioactive compounds (Table 5).

Ferulic acid (from Angelica sinensis), primarily targets mitochondrial structural organization by restoring the integrity of mitochondrial-associated membranes, thereby promoting functional coordination among mitochondrial biogenesis, mitochondrial fusion, and oxidative phosphorylation[157].

In contrast, Gypenosides (from Gynostemma pentaphyllum), Icariin (from Epimedium spp.), and Rosmarinic acid (from Rosmarinus officinalis) mainly enhance mitochondrial biogenesis through upregulation of PGC-1α, although their regulatory entry points and downstream effects are not identical. Specifically, gypenosides augment cellular antioxidant capacity via activation of the AMPK/Nrf2/HO-1 signaling pathway[158].

Whereas icariin, through stimulation of the Apelin/Sirt3 axis, and rosmarinic acid, via activation of the SIRT1/PGC-1α pathway, further improve mitochondrial functional status. These effects are reflected by restoration of ΔΨm, increased ATP production, and reduced ROS accumulation, collectively contributing to cardiomyocyte protection[96,159].

Regulation of ferroptosis by TCM

In DCM, ferroptosis have emerged as potential regulatory targets of TCM-derived bioactive compounds (Table 6).

Accumulating evidence indicates that bioactive compounds derived from TCM can suppress ferroptosis in DCM by targeting multiple interconnected regulatory nodes, primarily involving antioxidant defense, iron metabolism homeostasis, inflammation-associated oxidative stress, and lipid metabolism regulation.

Activation of the Nrf2-centered antioxidant defense system constitutes a common mechanism underlying the anti-ferroptotic effects of numerous TCM-derived bioactive compounds. Representative agents, including Baicalin (from Scutellaria baicalensis)[160], Luteolin (from Scutellaria baicalensis)[161], Isoliquiritigenin (from Glycyrrhiza uralensis)[162], Curcumin (from Curcuma longa)[163], and Sulforaphane (from Brassica oleracea)[124], enhance Nrf2 signaling and upregulate its downstream effector GPX4. This coordinated activation reinforces cellular antioxidant capacity, attenuates oxidative stress, and promotes cardiomyocyte survival.

Beyond antioxidant defense, certain TCM-derived bioactive compounds mitigate iron-dependent oxidative injury through direct regulation of iron metabolism.

Paeoniflorin (from Paeonia lactiflora)[164] not only activates the Nrf2/GPX4 pathway but also modulates gut microbiota composition, thereby reducing iron accumulation and suppressing the generation of ferroptosis-associated lipid ROS.

In addition, some TCM-derived bioactive compounds indirectly inhibit ferroptosis by alleviating inflammation-related oxidative stress. Andrographolide (from Andrographis paniculata)[165] suppress NF-κB-dependent inflammatory signaling while concurrently activating Nrf2-associated antioxidant responses, leading to reduced oxidative stress and attenuation of ferroptotic injury.

With respect to lipid metabolism regulation, several TCM-derived bioactive compounds confer cardioprotective effects in DCM by modulating lipid uptake and regulating GPX4 and SLC7A11 expression. For example, Astragaloside IV (from Astragalus membranaceus)[166] downregulates CD36-mediated lipid uptake, thereby alleviating iron overload, lipid peroxidation, and ferroptosis. Similarly, Schisandrol B (from Schisandra chinensis)[167] suppresses ferroptosis via modulation of the p53/SLC7A11/GPX4 axis, resulting in improved myocardial lipid metabolism.

Combination of individual TCM-derived bioactive compounds

An increasing body of evidence suggests that combinations of TCM-derived bioactive compounds frequently exert superior cardioprotective effects compared with monotherapy, potentially attributable to complementary regulation at critical mechanistic nodes or additive effects on interconnected signaling pathways.

In a DCM model, combined treatment with tilianin + syringin (from Dracocephalum moldavica and Panax ginseng) produced stronger cardioprotective effects than either compound alone. The combination more effectively improved cardiac pathological alterations and attenuated inflammation, oxidative stress, apoptosis, and mitochondrial dysfunction in diabetic rats and hyperglycemic H9c2 cells. Mechanistically, these effects were associated with coordinated regulation of the TLR4/MyD88/NF-κB/NLRP3 inflammatory axis and the PGC-1α/SIRT3-mitochondrial ROS signaling pathway. Notably, whereas tilianin or syringin monotherapy only partially improved selected molecular and functional parameters, their combined administration produced more comprehensive cardioprotection[168].

The combined administration of artemisinin and allicin (from Artemisia annua and Allium sativum) was more effective than either agent alone in improving cardiac function, alleviating myocardial fibrosis, and suppressing NF-κB signaling. This enhanced cardioprotective effect may be attributable to an additive inhibition of inflammation-related signaling pathways[169].

In addition, evidence suggests that the key bioactive compounds of the TCM formula SMYAD, chlorogenic acid and ferulic acid (from Lonicera japonica and Angelica sinensis), may attenuate cardiac lipotoxicity via the GCGR/PPARα and GCGR/AMPK signaling pathways, respectively. Through modulation of cardiac energy substrate utilization and amelioration of mitochondrial dysfunction, these TCM-derived bioactive compounds exert cardioprotective effects in DCM. Notably, both chlorogenic acid and ferulic acid act on shared molecular targets and exhibit partially overlapping signaling pathways; however, the referenced study did not directly compare their combined effects with those of single-compound interventions[170].

Collectively, these findings highlight the potential advantages of combination strategies involving individual TCM-derived bioactive compounds; nevertheless, the precise mechanisms underlying their superiority over single-agent applications remain to be further elucidated (Table 7).

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.

Application prospects of TCM formulations in DCM

Accumulating evidence indicates that Chinese herbal formulations ameliorate DCM by targeting distinct yet interconnected components of MQC. Ginseng Dingzhi decoction has been shown to restore mitochondrial homeostasis and enhance mitophagy-related signaling under hyperglycemic stress, thereby alleviating myocardial fibrosis and cardiomyocyte injury[171]. In parallel, Fufang Zhenzhu Tiaozhi protects diabetic hearts by modulating FFA uptake and lipid metabolism-related proteins, leading to normalization of mitochondrial dynamics[172]. Moreover, YuNü-Jian and Taohuajing primarily attenuate oxidative stress and inflammatory responses through activation of antioxidant signaling pathways, which may indirectly suppress a ferroptosis-permissive microenvironment in DCM[173,174]. Notably, evidence from a HFD-induced metabolic cardiomyopathy model further supports the therapeutic potential of Ling-Gui-Zhu-Gan decoction in metabolism-related myocardial injury via targeting ferroptosis[175]. Representative TCM formulations with cardioprotective effects in DCM are summarized in Table 8.

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.

LIMITATIONS AND TRANSLATIONAL CHALLENGES

Safety considerations and potential herb-drug interactions

The clinical application of TCM requires careful consideration of dose-response relationships. Certain TCM-derived bioactive compounds, such as rhein, exert hepatoprotective and nephroprotective effects within an appropriate therapeutic window, whereas excessive exposure has been associated with hepatotoxicity and nephrotoxicity[176]. Similarly, overdose of myristicin has been associated with hallucinations and other central nervous system manifestations[177]. These observations underscore that TCM safety is highly dose dependent.

Beyond intrinsic toxicity, the multitarget nature of TCM also raises concerns regarding herb-drug interactions (HDIs), particularly in patients with DCM who commonly receive concomitant antidiabetic and cardiovascular medications. HDIs may arise through pharmacokinetic mechanisms, including modulation of cytochrome P450 enzymes and drug transporters, or through pharmacodynamic interactions that result in additive or synergistic effects[178,179].

For example, berberine, a widely used alkaloid with glucose-lowering properties, has been reported to inhibit multiple CYP enzymes, potentially increasing systemic drug exposure and the risk of hypoglycemia when co-administered with antidiabetic agents[50,180]. Ginseng (Panax ginseng) and Cassia species has been reported to interact with antidiabetic drugs, potentially potentiating their hypoglycemic effects[180,181]. This could necessitate closer blood sugar monitoring and dose adjustments of antidiabetic medications to prevent hypoglycemia.

In the cardiovascular context, Danshen (Salvia miltiorrhiza) is widely used for cardiovascular conditions. It can potentiate the anticoagulant effects of warfarin through both pharmacokinetic and pharmacodynamic mechanisms, thereby increasing bleeding risk[182,183]. Ginseng may decrease the effectiveness of warfarin, potentially increasing the risk for blood clots, though some studies have shown no significant interaction. The presence of vitamin K in some ginseng preparations has been suggested as a contributing factor[184].

In addition to these commonly cited examples, the interaction potential of the major compounds highlighted in the therapeutic sections should also be specifically considered, particularly resveratrol and salidroside. Resveratrol may interact with co-administered drugs through modulation of drug-metabolizing enzymes and transporters. A review reported that, at relatively high doses (e.g., ≥ 1 g/day), resveratrol may inhibit multiple cytochrome P450 (CYP) isoforms, which could reduce the systemic metabolism of CYP substrate drugs and suppress intestinal first-pass metabolism, thereby increasing systemic exposure to certain co-administered agents[185]. Experimental evidence has also shown that resveratrol can increase the intestinal absorption of methotrexate by inhibiting intestinal P-glycoprotein and multidrug resistance-associated protein 2, while simultaneously reducing its renal clearance through inhibition of organic anion transporters 1 and 3[186]. By contrast, currently available in vitro evidence suggests that salidroside may have a relatively low drug-drug interaction potential. An in vitro assessment of biosynthetic salidroside found little evidence of clinically relevant interactions involving major CYP enzymes, monoamine oxidases, or organic anion transporting polypeptides at concentrations exceeding predicted plasma exposure[187]. Nevertheless, further pharmacokinetic and clinical studies are still needed to clarify its safety during concomitant use with other medications.

Thus, integrating TCM into the therapeutic regimen for DCM should be guided by a thorough risk-benefit assessment, careful patient selection, and close monitoring of possible adverse reactions. Multidisciplinary collaboration between cardiologists, endocrinologists, and traditional medicine practitioners is essential, alongside pharmacovigilance systems and targeted HDI studies to ensure safe clinical translation.

Oral bioavailability and pharmacokinetic challenges

Although TCM-derived bioactive compounds represent a promising source of cardioprotective agents, their translational application may be limited by challenges related to oral bioavailability and pharmacokinetics. For several compounds discussed in Tables 3, 4, 5, and 6, poor solubility, limited intestinal permeability, or extensive first-pass metabolism may reduce systemic exposure after oral administration[188,189]. Consequently, it remains unclear whether the concentrations achieved in vivo are sufficient to correspond to the effective concentrations reported in vitro. This limitation should be acknowledged when interpreting preclinical evidence and warrants further pharmacokinetic investigation.

For example, ginsenosides, the principal bioactive constituents of ginseng, generally show poor oral absorption and low bioavailability, partly owing to their relatively large molecular size and limited membrane permeability[190].

Several compounds summarized in Tables 3, 4, 5, and 6 have been investigated using bioavailability-enhancing strategies, including nanoformulations, lipid-based carriers, micelles, liposomes, solid dispersions, and phospholipid complexes, which may improve solubility, stability, intestinal absorption, and tissue delivery. Representative examples include curcumin[191,192], tanshinone IIA[193], andrographolide[194], luteolin[195], baicalin[196], icariin[197], astragaloside IV[198], and fucoxanthin[199]. In addition, some phytochemicals may exert pharmacological effects despite limited systemic exposure through alternative mechanisms, such as gut microbiota-mediated biotransformation into more bioactive metabolites, modulation of intestinal homeostasis, or actions of downstream metabolites, as exemplified by ginsenosides[200,201], curcumin[202], and baicalin[203].

To further illustrate the relationship between in vivo exposure and pharmacological activity, resveratrol provides a well-studied example. Pharmacokinetic studies in humans have shown that following oral administration of 0.5-5 g, free resveratrol transiently reaches low micromolar plasma concentrations (Cmax ≈ 2.36 μmol/L at 5 g), whereas its glucuronide and sulfate conjugates circulate at three- to eightfold higher levels, with AUC values up to 23 times greater than the parent compound[204]. These conjugates may function as metabolic reservoirs, as sulfatases and β-glucuronidases can locally regenerate free resveratrol at target tissues[205]. In diabetic rat models, chronic administration resulted in detectable myocardial levels of resveratrol-3-sulfate (approximately 0.05 nmol/g) and resveratrol-3-glucuronide (approximately 0.01 nmol/g), both associated with improved cardiac function[206]. Moreover, recent evidence indicates that gut microbiota contribute significantly to resveratrol metabolism; a resveratrol reductase identified in Eggerthella lenta produces stable secondary metabolites that enhance tissue exposure and pharmacological activity[207]. Together, these mechanisms may help explain the possible cardioprotective effects of resveratrol despite its limited systemic exposure.

OUTLOOK AND FUTURE PERSPECTIVES

Looking ahead, several key challenges remain. First, early-stage DCM often presents with non-specific symptoms and lacks reliable diagnostic criteria. There is an urgent need to establish sensitive, specific, and early diagnostic biomarkers. Currently, iron homeostasis is assessed indirectly via serum iron, ferritin, and transferrin saturation, while targeted assays for MQC or ferroptosis pathways remain underdeveloped. Future diagnostic frameworks should incorporate early biomarkers capable of detecting mitochondrial dysfunction and ferroptotic stress, which may serve as both diagnostic tools and therapeutic evaluation metrics.

Second, treatment of DCM remains primarily symptom-driven, with most therapies focused on glycaemic and lipid control. Innovative drug development should prioritize interventions that address mitochondrial dysfunction, ferroptosis - offering personalized solutions aligned with individual pathophysiological profiles.

Given the complexity of DCM, combination therapy is likely to become a predominant therapeutic strategy. In this context, precision medicine does not necessarily equate to single-target intervention, but rather to the rational and context-specific modulation of multiple key pathogenic nodes. Current clinical data suggest synergistic benefits from combining SGLT2 inhibitors with GLP-1RAs. Future research should systematically investigate multi-level combination therapeutic strategies, including synergistic combinations among mechanism-oriented agents (e.g., iron chelators with antioxidants or mitochondrial protectants) and the integration of novel mechanism-targeted therapies with established standard treatments (e.g., ferroptosis inhibitors combined with SGLT2 inhibitors)[208]. Recent clinical evidence for chelation-based approaches in this context remains limited. In the 2024 TACT2 randomized clinical trial, EDTA-based chelation in patients with diabetes and previous myocardial infarction lowered blood lead levels but did not reduce major adverse cardiovascular events, highlighting the need for caution when extrapolating chelation-based approaches to DCM[209]. Evaluate how these synergistic therapies can enhance efficacy while minimizing adverse effects[210]. While preclinical data suggest that co-administration of ferroptosis inhibitors (e.g., FSP1) with mitochondrial stabilizers (e.g., CoQ10) may synergistically reduce oxidative stress and mitigate ferroptotic cell death[37], clinical translation of such combination therapies remains challenging. Prolonged or high-dose use of iron chelators has been associated with hepatotoxicity, nephrotoxicity, and hypersensitivity reactions[211-214]. Additionally, potential pharmacokinetic and pharmacodynamic interactions among mitochondrial-targeted agents warrant careful evaluation. Therefore, robust preclinical studies are necessary to establish the safety and efficacy of such combination strategies prior to their routine clinical implementation.

Studying the pharmacodynamic and pharmacokinetic interactions, as well as the potential additive or synergistic effects, will help optimize treatment regimens. Such personalized combination therapies not only enhance clinical outcomes but also expand the therapeutic toolkit to meet individual patient needs.

More broadly, the poor solubility, rapid clearance, and extensive first-pass metabolism of many TCM-derived bioactive compounds remain major obstacles to clinical translation. To address these limitations, advanced formulation strategies have been investigated. For instance, a berberine hydrochloride-loaded self-microemulsifying drug delivery system (BH-SMEDDS) has significantly improved oral bioavailability in preclinical studies[215]. Such formulation-based approaches hold promise for enhancing the translational potential of TCM-derived bioactive compounds in cardiovascular disease management.

Nevertheless, most current research remains confined to cellular and murine models, which capture only selected aspects of DCM[216]. The lack of validation in human myocardial tissues and across species continues to limit clinical translation[217], underscoring the need for multidisciplinary collaboration to more effectively integrate mechanistic insights, therapeutic strategies, and translational research. Emerging human cell-based systems, such as human induced pluripotent stem cell-derived cardiomyocytes, offer promising translational platforms to bridge this gap, although their use remains limited[218].

Finally, leveraging cutting-edge platforms - such as bioinformatics, systems biology, and multi-omics technologies - offers a powerful approach to identify, refine, and optimize new treatment candidates with improved efficacy and safety. The continued exploration of biologics and TCM, including their mechanistic pathways and synergistic potential. For instance, integrated metabolomic and transcriptomic analyses have been used to explore the cardioprotective mechanisms of salvianolic acid B in DCM, suggesting coordinated regulation of metabolic pathways (e.g., carnitine synthesis and fatty acid oxidation) and ferroptosis-related signaling[167]. These strategies are expected to accelerate the development of next-generation therapeutics tailored to the complex pathophysiology of DCM.

CONCLUSION

DCM is not driven by a single pathological process. Accumulating evidence indicates a bidirectional crosstalk between ferroptosis and mitochondrial dysfunction. They represent central pathogenic mechanisms in the development of DCM[219].

In this review, we delineated the interconnected roles of iron regulation, mitochondrial dynamics, mitophagy, and biogenesis in DCM pathogenesis, and assessed the therapeutic potential of three major intervention categories: Standard glucose-lowering agents, novel mechanism-targeted therapies (iron chelators, mitochondrial protectants) and multi-targeting TCM and their bioactive compounds. Notably, monotherapies such as resveratrol and Salidroside have demonstrated dual regulatory effects on mitochondrial homeostasis and ferroptosis in preclinical models.

Given the multifactorial nature of DCM, combination therapies or multitarget TCM-based approaches are likely to emerge as predominant treatment paradigms. Although preclinical findings are encouraging, substantial challenges remain for clinical translation. Future studies may enhance translational relevance by incorporating advanced disease models, such as human induced pluripotent stem cells, and by leveraging multi-omics technologies to identify key therapeutic targets of TCM, critical pathogenic drivers of DCM, and robust biomarkers, thereby enabling optimized patient stratification.

Overall, accumulating evidence supports ferroptosis and mitochondrial dysfunction as hallmark features of DCM and highlights their promise as targets for mechanism-based therapeutic intervention.