Under normal physiological conditions, FAs are the primary energy substrate for the heart, while glucose metabolism typically plays a secondary role (30). However, in response to pathological damage, particularly cardiac toxicity, glucose metabolism can rapidly become the primary energy source, at least in the early stages. In DIC, changes in glucose metabolism are particularly pronounced and these metabolic alterations play a significant role in the cardiac damage caused during DOX treatment. Early studies indicate that DOX treatment initially increases glucose uptake in myocardial cells, but this effect is followed by a significant decrease (31). This brief activation of glucose uptake is closely associated with the recruitment of the glucose transporter GLUT1 to the plasma membrane. However, DOX downregulates the expression of GLUT1, leading to reduced glucose uptake and exacerbating myocardial damage (32). This metabolic disruption suggests that the inhibition of glucose metabolism may be a key mechanism underlying DOX-induced cardiac dysfunction.

The activation of glycolysis occurs through a phosphorylation process mediated by fructose-6-phosphate-2-kinase (PFK2). PFK2 catalyses the synthesis of fructose-2,6-bisphosphate, a key allosteric activator of fructose-6-phosphate-1-kinase in myocardial cells, thereby driving glycolysis forward. Research has indicated that DOX exposure inhibits PFK activity, directly affecting the efficiency of glycolysis and further exacerbating myocardial damage (33). Worse still, the downregulation of key enzymes in glycolysis leads to the accumulation of metabolites and a decrease in pH within myocardial cells. This may initiate a vicious cycle that reduces the activity of rate-limiting glycolytic enzymes and ultimately threatens myocardial energy supply, resulting in HF (19). Additionally, DOX has been found to enhance glycolysis and abnormal metabolic processes by activating the expression and activity of carbonic anhydrase (CA12) (34). The upregulation of CA12 promotes the activation of glycolytic pathways in myocardial cells, thereby enhancing ATP production. This appears to be a compensatory mechanism adopted by cardiac cells in response to low-energy states. Notably, the CA12 antagonist Indisulam has been shown to effectively alleviate DIC, demonstrating good protective effects in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes, engineered cardiac tissues and animal models (34). These findings suggest that although DOX causes disruptions in cardiac energy metabolism, intervening in the glycolytic process may help mitigate its harmful effects to a certain extent.

Furthermore, increasing evidence suggests that DIC may be linked to insulin signalling dysregulation and cardiac insulin resistance. Animal model studies show that the onset of cardiac insulin resistance is often accompanied by impaired oxidation of glucose, lactate and FAs, and is one of the early markers of cardiac stress (35). Under normal conditions, the insulin signalling pathway regulates cardiac energy metabolism by promoting glucose uptake and oxidation. Insulin enhances glucose uptake, which is then converted into pyruvate through glycolysis, absorbed by the mitochondria and converted into acetyl-CoA, which further enters the TCA cycle for energy production. However, insulin can also directly enhance mitochondrial glucose oxidation, independent of glucose uptake and glycolysis (36). Concern arises as desensitisation of insulin signalling often leads to inhibition of glucose uptake, which has been recognized as a major risk factor for HF. Such abnormal changes in insulin signalling disrupt the metabolic adaptability of the heart, potentially leading to a worse prognosis (19). While insulin sensitisers have shown potential in certain clinical applications, they have not significantly improved patient outcomes and these drugs may carry cardiovascular side effects, increasing the risk of their use (37).

Overall, DOX-induced glucose metabolism dysregulation is a key component of DIC, leading to cardiac energy metabolic disturbances by altering glucose uptake, glycolysis and mitochondrial oxidation processes.

FAO serves as the primary energy source for a normal heart and its disruption is closely associated with the development of myocardial damage (38). DOX may significantly contribute to the initiation of DIC by impairing energy metabolism pathways, particularly through the inhibition of FAO. For instance, a rat study showed that DOX inhibits carnitine palmitoyl transferase 1 (CPT1), thereby preventing long-chain FAs from entering the mitochondria and inhibiting FAO (39). Additionally, changes in cellular gene expression are considered a fundamental cause, as a mouse model revealed that DOX reduces the cardiac expression of peroxisome proliferator-activated receptor α, a key regulator of β-oxidation (40). Furthermore, it was found that DOX inhibits the expression of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), potentially favouring a glycolytic state over FAO and suggesting a loss in mitochondrial biogenesis (40).

In the heart, activation of AMP-activated protein kinase (AMPK) is a crucial component of the metabolic adaptive response to myocardial injury, stimulating ATP production through catabolic processes to maintain cellular energy balance (41). In cardiomyocytes, AMPK not only promotes glucose uptake by activating glucose transporter GLUT4 on the cell membrane, but also increases FA uptake by translocating FA transporter CD36 vesicles to the plasma membrane (42). Once inside the cell, AMPK not only promotes glucose metabolism through glycolysis but also enhances FA metabolism by facilitating its entry into mitochondria and its breakdown via β-oxidation (43). Furthermore, AMPK inhibits the activity of acetyl-CoA carboxylase 2, reducing malonyl-CoA levels and thereby alleviating the inhibition on FA entry into mitochondria via CPT1 (44,45). This process is the rate-limiting step in β-oxidation, and thus, activation of AMPK promotes FAO. In various in vivo experimental models, DOX has been repeatedly shown to inhibit cardiac AMPK, although the exact mechanism of inhibition remains unclear. The role of AMPK in DIC has been previously reviewed (46).

DOX exacerbates myocardial injury by inhibiting AMPK activity, thereby disrupting FAO and other metabolic pathways. In DIC, abnormal suppression of AMPK leads to severe changes in cardiac metabolism, further exacerbating the decline in myocardial function. Therefore, regulating AMPK activity to restore normal function in FAO and other metabolic pathways may provide novel therapeutic strategies for DIC.

KBs, including β-hydroxybutyrate (β-OHB), acetoacetate and acetone, have emerged as important substrates for intrahepatic synthesis and extrahepatic use in energy metabolism. The high efficiency of KBs as an energy supply makes them crucial components in cardiac metabolic regulation (47). KBs were reported may have higher energy efficiency than FAs, producing more energy per oxygen molecule consumed. This characteristic may have potential benefits for managing HF (48). The common occurrence of ketosis and increased myocardial ketone oxidation in patients with HF suggests that enhancing ketone delivery may improve outcomes in HF (49). This finding has driven research into using either endogenous ketogenesis or exogenous ketone supplementation as therapeutic strategies for HF (50-52).

β-OHB is one of the KBs synthesised in the liver and serves as an energy source when energy is limited or in individuals with ketogenic diets. β-OHB has been found to offer various health benefits, including reducing hypertension and delaying vascular ageing. Studies show that β-OHB can inhibit the acetylation of mitochondrial proteins by modifying the acetyl-CoA pool, which subsequently reduces FA intake (53). This process leads to anti-inflammatory benefits, reduces collagen deposition and improves mitochondrial function in the heart of mice with HF with preserved ejection fraction (54). Likewise, another study indicated that administration of exogenous β-OHB significantly reduced cardiac fibrosis and increased cardiac output in both control and DOX-induced cardiotoxicity mouse models (55). These studies suggest that β-OHB can improve cardiac function by enhancing cardiac output and reducing cardiac fibrosis, especially in DOX-induced cardiotoxicity models.

Using KBs as substrates for cardiac energy metabolism has become a promising research direction. With ongoing research into the benefits of KBs in the treatment of HF, they may provide novel therapeutic approaches for improving the prognosis of patients with HF. The energy benefits of KBs, particularly β-OHB, offer novel therapeutic strategies for DIC, potentially providing improved cardiac protection by improving cardiac metabolism, reducing inflammation and alleviating fibrosis.

The oxidation of AAs represents a potentially important source of ATP production, particularly in the heart. One specific type of AA oxidation that has been extensively studied is the oxidation of branched-chain AAs in the heart (56). Of note, a recent study showed that the levels of AAs, including arginine, ornithine, glutamine, histidine, lysine and proline, were elevated in the serum of individuals with DIC, suggesting that disorders of AA metabolism have a significant role in the development of this condition (27). Of these AAs, the levels of ornithine were found to be highly negatively correlated with ejection fraction and fractional shortening, while also being positively correlated with the levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) (27). Similarly, arginine levels are also highly positively correlated with CK-MB and LDH, further highlighting the critical role of arginine and ornithine in DIC. The elevated levels of these AAs reflect increased protein degradation and/or dysregulation of AA metabolism in DIC, providing a plausible explanation for the impaired cardiac contractile function. Specifically, arginine, ornithine, glutamine and α-ketoglutarate participate in the biosynthesis of arginine, while arginine, ornithine and proline are involved in the metabolism of arginine and proline. Of note, arginine, as a substrate for arginase, has been found to have elevated circulating levels of arginase in patients who have HF. Inhibition of arginase has been shown to enhance the basic contractile ability of isolated cardiac cells, further highlighting the important role that AA metabolism may play in the development of cardiac dysfunction (57). Methionine (Met), an essential AA, is closely associated with various metabolic processes, including the synthesis of proteins, one-carbon metabolism and redox maintenance. Previous research has reported that Met has cardioprotective effects in type 2 diabetes via regulating one-carbon metabolism and methylation status (58). Recently, Xin et al (59) investigated the efficacy of Met in a mouse model of DOX-induced myocardial injury. Met supplementation improved cardiac dysfunction by maintaining mitochondrial integrity and function through modulating mitophagy activity. However, whether Met participates in DIC by regulating the one-carbon cycle needs further study.

With the framework of DIC, the elevation of AAs may be associated with a decrease in oxidative metabolism. The increase in glycolytic activity and the decrease in FA utilisation could be the result of reduced oxidative metabolism, leading to a mismatch between FA absorption and utilisation. The imbalance in FA metabolism may negatively affect the energy supply to myocardial cells, further exacerbating cardiac dysfunction (Fig. 2).

The mitochondrial respiratory chain plays a critical role in energy production by coupling electron transfer between its complexes with proton transport across the inner mitochondrial membrane, generating the electrochemical gradient essential for ATP synthesis (62). Findings from both in vivo and in vitro studies suggested that DOX disrupts the activity of ETC complexes I, II and IV, as well as NADH dehydrogenase and cytochrome C oxidase, leading to impaired mitochondrial energy production and changes in mitochondrial permeability transition (29,63,64). Cytochrome C oxidase subunit 5A (COX5A), a nuclear-encoded component of the terminal oxidase in the mitochondrial respiratory chain, has been found to be downregulated in DOX-treated H9c2 cells. Interestingly, COX5A overexpression mitigated DOX-induced mitochondrial dysfunction (65). Prohibitin 2 (PHB2), a mitochondrial membrane protein, is crucial for maintaining mitochondrial bioenergetics (66). Research by Yang et al (64) revealed that PHB2 overexpression significantly enhanced mitochondrial function and reduced DIC severity. Mechanistically, PHB2 was shown to interact directly with NADH-ubiquinone oxidoreductase core subunit V2, a key component of complex I, to stabilise its expression, thereby supporting mitochondrial OXPHOS and energy production (64).

Beyond energy generation, the respiratory chain is also a major source of intracellular ROS, produced as byproducts of electron transfer (60). ROS formation begins with the one-electron reduction of the quinone portion of NADH dehydrogenase on complex I. During this process, the quinone ring of DOX accepts an electron, forming a semiquinone that subsequently generates superoxide anions. Superoxide dismutase converts these anions to hydrogen peroxide, which can further produce hydroxyl radicals through enzymatic redox cycling (60). Of note, a complex interaction exists between mitochondrial OXPHOS and ROS production. OXPHOS provides the necessary energy for the cell; however, excessive ROS production can damage the mitochondria, further impairing energy metabolism. DOX inhibits mitochondrial respiratory chain function, reducing ATP generation while increasing ROS production (67). This dual impact not only impairs myocardial cell function but also exposes cells to greater metabolic stress, ultimately leading to HF. Ferroptosis is a non-apoptotic regulatory cell death characterised by iron-dependent lipid peroxide accumulation, which is regulated by multiple cellular metabolic pathways, including redox steady state, iron metabolism, mitochondrial activity and glycolipid and AA metabolism (68,69). Previous research has reported that mitochondria are the primary site of DOX-induced ferroptosis (70). DOX promotes mitochondrial iron overload by the formation of DOX-Fe²⁺ complexes, disrupting iron homeostasis and triggering lipid peroxidation on mitochondrial membranes, and ultimately leading to myocardial ferroptosis. A growing body of evidence indicates that targeting ferroptosis is a promising therapeutic strategy, as described in reviews by Wu et al (71) and Yi et al (72).

Thus, modulating the balance between mitochondrial OXPHOS and ROS generation may be a key strategy for mitigating DIC (73). For instance, targeting mitochondrial antioxidants (such as superoxide dismutase) or enhancing mitochondrial ATP synthesis could help alleviate cardiac damage during DOX treatment, protecting myocardial cells from ROS-induced harm (74).

MQC is a crucial cellular self-regulation process, encompassing mitochondrial protein synthesis and folding, mitophagy, mitochondrial dynamics and mitochondrial biogenesis (75). The stability of mitochondrial content and function is tightly regulated by MQC. Previous research indicated that MQC is crucial in DIC, with potential therapeutic drugs targeting related processes (76). DOX aggravates mitochondrial DNA damage by activating p53, which then binds to the promoters of PGC-1α and PGC-1β, inhibiting their expression and suppressing mitochondrial biogenesis, thereby affecting mitochondrial energy production (77). Resveratrol, a natural polyphenolic compound, upregulates PGC-1α and Sirtuin 1 levels, enhances deacetylation, and activates PGC-1α function, thereby promoting mitochondrial biogenesis and FAO, providing protection against DIC (78). In addition, previous evidence reported that AMPK is associated with mitochondrial homeostasis, including mitochondrial biogenesis (79). Studies have shown that AMPK is phosphorylated and activated under metabolic stress (e.g., DOX) and the activated AMPK promotes the expression of PGC-1α, which leads to the enhancement of mitochondrial biogenesis and oxidative capacity (46,80).

In addition to mitochondrial biogenesis, the regulation of mitochondrial dynamics is also crucial in DIC (81,82). Mitochondrial dynamics are controlled by fusion-related proteins, including mitofusin 1/2 (Mfn1/2) and optic atrophy 1, as well as fission-related proteins such as dynamin-related protein 1 (Drp1) and fission 1 (83,84). Research has indicated that DOX treatment increases serine 616 phosphorylation of Drp1 in both mouse cardiac tissue and H9c2 cardiomyocytes, promoting mitochondrial fission. Conversely, either knocking out Drp1 or using LCZ696 as a pretreatment to decrease Drp1 phosphorylation effectively blocks DOX-induced mitochondrial fission and apoptosis (85). These findings highlight the significance of Drp1-driven mitochondrial fission in DOX-induced cardiomyopathy. Alterations in fusion proteins, such as Mfn2, are also pivotal in DIC. For instance, one study demonstrated that mitochondrial fusion mediated by Mfn2 enhances oxidative metabolism, minimises cellular damage and mitigates mitochondrial oxidative stress in cardiomyocytes exposed to DOX (86). Further research suggests that Mfn2 facilitates the transition from aerobic glycolysis to mitochondrial oxidative metabolism (86). Targeting fusion mechanisms regulated by Mfn2 may serve as a strategy to prevent DIC while augmenting anti-cancer effects through metabolic reprogramming. Furthermore, He et al (87) demonstrated that PGAM family member 5, mitochondrial serine/threonine protein phosphatase disturbs mitochondrial dynamics by mediating DRP1 dephosphorylation at Ser637 and exacerbating Mfn2 downregulation, thus aggravating DIC.

Mitophagy is an important cellular process that involves selectively wrapping and degrading damaged or dysfunctional mitochondria in cells to maintain mitochondrial homeostasis (88,89). This process can be categorised into two mechanisms: PINK1/Parkin-dependent and receptor-dependent pathways (90). The latter pathway relies on the participation of specific mitophagy receptors, including Bnip3, Nix and FUN14 domain containing 1 (FUNDC1) (90). Multiple studies have consistently shown that DOX induces abnormal mitophagy in cardiomyocytes, which disrupts ATP production, mPTP opening, and ultimately results in cell death (91,92). The activation of phosphatase and tensin homolog-induced kinase 1 (PINK1)/Parkin signalling is reported to be associated with P53. When p53 is activated by DOX, it can interact with Parkin in the cytoplasm, thus inhibiting mitophagy (91). Sestrin 2 (SESN2), a protein activated by stress and associated with mitochondrial function, engages with Parkin and p62 to facilitate Parkin recruitment to the mitochondria, initiating mitophagy (93). Another study demonstrated that increased SESN2 activity exerted a protective effect against mitochondrial dysfunction and cardiotoxicity induced by DOX (93).

He et al (94) indicated that FUNDC1-mediated mitochondrial-endoplasmic reticulum contacts exerted a cardioprotective effect by inhibiting autophagosome biogenesis and reducing oxidative stress. Notably, recent findings emphasised the role of TANK binding kinase 1 in mitochondrial damage and cardiotoxicity linked to DOX, potentially through its phosphorylation activity and sequestosome 1/p62-mediated mitophagy (95). Similarly, Lu et al (96) revealed that follistatin-like protein 1 mitigated DOX-induced cardiomyopathy by suppressing methionine sulfoxide reductase B2-dependent mitophagy. It is worth noting that although a large number of studies have shown that mitophagy plays an important role in DIC (97), the mechanism of how cardiomyocytes coordinate the use of various pathways of mitophagy remains elusive.

Metabolomics, an interdisciplinary field combining analytical chemistry, technological platforms and mass spectrometry, has become a critical tool for discovering novel biomarkers and monitoring biological processes (99). These techniques offer detailed analysis of plasma metabolites at different time-points during treatment, potentially identifying early metabolic changes before cardiac damage occurs. Early identification of cardiac toxicity biomarkers, particularly in cancer treatment, is crucial for reducing treatment risks and improving patient prognosis (100).

In a study involving 38 patients with HER2⁺ breast cancer receiving anthracycline therapy, liquid chromatography-mass spectrometry was used to analyse fasting plasma samples at various time-points during treatment (101). The results showed that before functional changes were detected by echocardiography, plasma levels of citrate and aconitate were significantly lower in patients who later developed cardiac toxicity compared to those who did not (101). Although the study did not further assess the predictive value of these metabolites, it suggests that citrate and aconitate could serve as potential biomarkers. Recently, Thonusin et al (102) performed a clinical study of 64 patients with breast cancers (HER2⁺ and HER2⁻) treated with DOX; blood plasma metabolomes indicated that 33 metabolites were altered in HER2⁺ patients, while 29 metabolites were altered in HER2⁻ patients. Further correlation analysis showed that the changes of these metabolites were related to cardiac function indices such as left ventricular ejection fraction (LVEF) and plasma TnI, suggesting that plasma metabolomes may be effective markers for DIC. In a prospective cohort study of 170 patients with breast cancer treated with DOX, Finkelman et al (103) indicated that early alterations in arginine-nitric oxide metabolite levels and early biomarker changes were associated with acute cardiotoxicity.

Similarly, Xue et al (27) observed 41 differential metabolites involved in FAO and the TCA cycle in a mouse model of DOX-induced toxicity, which were closely associated with DIC. These evidences further highlight that early metabolic changes in the citric acid cycle may serve as important plasma biomarkers for DIC. Furthermore, Thonusin et al (104) investigated the efficacy of serum metabolomes as potential non-invasive biomarkers for DIC in Wistar rats. Metabolomic analysis showed that the level of 26 serum metabolomes were lower and 33 serum metabolomes were higher in DOX-treated rats compared with the control. Further correlation analysis showed that the changes of these metabolites were related to cardiac function indices, such as LVEF, E/A ratio and cardiac (c)TnI (104).

In addition to plasma metabolite biomarkers, modern imaging technologies are playing an increasingly important role in the early diagnosis of myocardial damage. Emerging techniques such as myocardial strain imaging via echocardiography, cardiac magnetic resonance myocardial strain imaging and positron emission tomography (PET)/CT imaging are becoming widely used in clinical settings to monitor DIC progression (105). ¹⁸F-fluorodeoxyglucose (FDG) PET/CT, which is used to evaluate glucose metabolism in tissues and organs, has distinct advantages in clinical applications. Patients with cancer undergoing ¹⁸F-FDG PET/CT typically fast for 4-6 h to suppress glucose uptake by tissues, making it useful for detecting metabolic changes before cardiac damage occurs. Studies have shown increased ¹⁸F-FDG uptake in the left ventricular myocardium of patients with Hodgkin lymphoma treated with DOX, suggesting an association between increased glucose uptake and DIC (106,107). Overall, although the availability and cost of ¹⁸F-FDG PET/CT remain limiting factors, its diagnostic potential is substantial. This advancement represents a significant step forward in understanding DIC, offering potential for early detection and improved prognosis for patients undergoing chemotherapy (Table I).

Metformin, a commonly used drug for treating type 2 diabetes, has recently been shown to provide direct cardiac protection against DIC through the activation of the AMPK signalling pathway. In vitro studies have suggested that AMPK activation is a critical factor by which metformin exerts its cardioprotective effects. The use of AMPK inhibitors can abolish the protective effects of metformin, underscoring the central role of AMPK in this process (122). Furthermore, AMPK activation can reverse the toxic effects of DOX, potentially by acting as a sensor of energy stress to alleviate oxidative stress, thereby protecting cardiomyocytes from damage (123). Specifically, DOX treatment leads to the inactivation of the AMPK signalling pathway and downregulation of platelet-derived growth factor receptor (PDGFR) expression. However, metformin treatment can restore PDGFR expression, thereby activating the AMPK pathway (124). Additionally, metformin reduced H₂O₂ levels, alleviated mitochondrial damage and maintained the expression of autophagy markers (such as light chain 3B-II and p62) through AMPK activation, ultimately improving cardiac function (125). A retrospective cohort study by Onoue et al (126) reported that metformin treatment reduced the incidence of HF and overall mortality in patients with diabetes receiving DOX after 1 year. Recently, Serageldin et al (127) reported a clinical study of 70 non-diabetic women with breast cancer who were treated with 240 mg/m² DOX. Metformin (1,700 mg/day) therapy significantly abrogated the decrease in LVEF caused by DOX (65.9 vs. 62.2%; P<0.0007) (127).

Statins are widely prescribed for cardiovascular conditions such as atherosclerosis and coronary heart disease (128). Research has indicated that it can also activate AMPK signalling in cardiac tissue, which exerts a cardioprotective effect (129). This pathway involves reactive nitrogen species and the Ras-related protein Rac1. Pitavastatin has been shown to inhibit Rac1 activity, providing cardiac protection by decreasing apoptosis in heart muscle cells and improving contractile function in a DIC mouse model (130). Similarly, other statins, including lovastatin and rosuvastatin, have demonstrated cardioprotective effects (131,132).

Natural compounds are another important source of cardiac protection via AMPK modulation (9). For instance, epigallocatechin gallate, a bioactive natural compound with antitumor, anti-inflammatory and antioxidant properties, has been shown to enhance anti-cancer effects and reduce DIC by upregulating AMPKα2 activity, thereby promoting energy supply (133). Furthermore, oleuropein, a phenolic compound derived from olives, has shown potential in alleviating DIC (134). Studies suggest that oleuropein protects the heart by modulating myocardial metabolism, although its precise mechanisms require further investigation (135,136). Betaine has been shown to ameliorate DOX-induced cardiomyopathy by inhibiting oxidative stress, inflammation and fibrosis via modulation of the AMPK/nuclear factor erythroid 2-related factor 2/TGF-β pathway (137). Similarly, Linggui Zhugan decoction, a Traditional Chinese Medicine formulation, has been reported to ameliorate mitochondrial damage of DIC via regulation of the AMPK-forkhead box O3a pathway by targeting BTG anti-proliferation factor 2 (138). Notably, certain high-energy phosphate compounds such as phosphocreatine play an important role in cellular energy homeostasis and mitochondrial function. A recent study confirmed that phosphocreatine ameliorated cardiac damage and preserved mitochondrial function via regulation of the AMPK/PGC-1α pathways (139). Similarly, Liu et al (140) demonstrated that melatonin alleviated mitochondrial oxidative damage via modulation of the AMPK/PGC1 pathway, thereby alleviating acute DIC. In conclusion, targeting AMPK represents a promising strategy for treating DIC (Fig. 3). However, the lack of extensive clinical trials and potential drug safety concerns needs to be addressed.

More recently, therapeutic strategies targeting mitochondrial dysfunction have gained significant attention and show considerable potential. For example, the DRP1 inhibitor Mdivi-1 has been shown to alleviate DOX-induced mitochondrial damage and cardiomyocyte apoptosis (141). Additionally, the angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) not only protects against the effects of cardiac failure but also mitigates DIC by modulating mitochondrial dynamics (85). Dhingra et al (142) indicated that ellagic acid reduced DOX-induced Drp1 phosphorylation, prevented mitochondrial fission and decreased cardiomyocyte death. Similarly, another study found that liensinine suppressed DIC through inhibition of Drp1-mediated maladaptive mitochondrial fission (143). Furthermore, drugs targeting MFN2, such as paeonol and cyclosporine A, have demonstrated cardioprotective effects, primarily through promoting mitochondrial fusion and mitigating DOX-induced mitochondrial dysfunction (144,145). Ivabradine has been shown to improve mitochondrial function and cardiac calcium homeostasis, thereby preserving DIC (146). Recently, the Rho family GTPase 3 (Rnd3) was reported to significantly impede Drp1-induced mitochondrial fission, thereby mitigating DOX-induced PANoptosis. Mechanistically, Rnd3 directly interacts with Rho-associated kinase 1 in the cytoplasm, which, in turn, inhibits Drp1 phosphorylation at Ser616 and consequently inhibits mitochondrial fission (147).

Mitophagy has also emerged as a critical feature of DIC and a growing area of research. Numerous studies suggest that several natural compounds and drugs can alleviate DIC by modulating mitophagy. For instance, luteolin has been found to enhance autophagosome formation and lysosome production, improving DOX-induced mitochondrial dysfunction and cardiomyocyte damage (148). Another study revealed that the GLP-1 receptor agonist semaglutide mitigated DIC by enhancing BNIP3-mediated mitophagy (149). Metformin attenuates DIC by improving mitochondrial dynamics and calcium homeostasis (150). Vericiguat activates the PRKG1/PINK1/STING signalling pathway to improve mitophagy, alleviating DIC symptoms (151). Urolithin A significantly alleviates DIC by increasing autophagy and beclin 1 regulator 1 expression and promotes PINK1-mediated mitophagy (152). A recent study indicated that isoliquiritin (ISL) exerted cardioprotective effects in mice treated with DOX. Mechanistically, ISL attenuated DOX-induced macro-autophagy-dependent protein homeostasis by improving BNIP3-mediated mitophagy (153).

In conclusion, therapeutic strategies targeting mitochondrial dysfunction, particularly those focused on mitochondrial dynamics and mitophagy, provide novel avenues for treating DIC. These approaches hold promise not only for mitigating DIC but also for offering novel treatment options for other cardiovascular diseases associated with mitochondrial dysfunction (Fig. 4).

Exercise training, an effective non-pharmacological therapeutic strategy, is beneficial in multiple cardiovascular diseases (154). Numerous preclinical and clinical investigations have shown that exercise interventions have the ability to reduce DIC (155). In parallel, a clinical randomised controlled trial reported that exercise training was safe during chemotherapy and significantly improved the cardiorespiratory fitness of patients with breast cancer (156). Previous evidence indicated that exercise alleviated DIC via several potential mechanisms, such as ROS damage, energy metabolism alteration and cell death (157). AMPK, as a metabolic regulator, is not only activated by drugs, but is also affected by exercise in DIC (46). A study found that endurance exercise preconditioning alleviated DOX-induced ferroptosis of cardiomyocytes through mitochondrial superoxide-dependent AMPKα2 activation (158). Emerging evidence indicates that exercise enhances cardiac mitochondrial rejuvenation and remodelling by promoting mitochondrial biogenesis, fusion and mitophagy, contributing to protection against DIC (22). Additionally, aerobic exercise mitigates DIC by inhibiting the activation of the NLR family pyrin domain containing 3 inflammasome in a rat model (159). Notably, recent findings reveal that exercise training defends against DIC by increasing the expression of Fcγ receptor IIB in B cells, which plays a significant anti-inflammatory role and contributes to the protective effects of exercise in DIC (160). These findings suggest that exercise may serve as a potential strategy for cardioprotection in DIC.

In addition to exercise, intermittent fasting has surfaced as an innovative health interventional strategy, drawing widespread attention for its potential in managing cardiovascular diseases. Recently, a study showed that sustained alternate-day fasting could affect DIC (161). Fasting regulates various cellular metabolic pathways and autophagic processes, enhancing cellular stress tolerance and repair capacity. Nevertheless, the study suggested that prolonged alternate-day fasting may negatively impact the heart's ability to counteract the cardiotoxic effects of DOX (162). Recently, Cortellino et al (163) reported that fasting had positive effects in cancer prevention and treatment, as well as reducing cardiotoxicity. This highlights the need for further research to weigh the safety and effectiveness of fasting in cardiovascular disease treatment.

Mitochondrial transplantation has become a novel therapeutic option and a promising approach for treating DIC (164). Mitochondrial transplantation involves introducing healthy mitochondria into damaged cardiomyocytes to replace dysfunctional mitochondria, restoring energy metabolism and biosynthesis, ultimately improving heart function (165). Existing experimental data indicate that mitochondrial transplantation effectively improves myocardial ischemia-reperfusion injury and DIC in animal models and in vitro studies (166). For instance, Maleki et al (167) were the first to apply mitochondrial transplantation in DIC research and successfully restored the activity of neonatal rat cardiomyocytes (167). In parallel, in another in vivo study where mitochondria isolated from healthy liver tissue were injected into the tail vein of Wistar rats treated with DOX (10 mg/kg), fluorescence imaging confirmed that exogenous mitochondria were taken up by cardiomyocytes within 24 h of administration. Further analysis confirmed that mitochondrial transplantation ameliorated DOX-induced cardiac dysfunction by reducing ROS production, lipid peroxidation and inflammation (168). Similarly, Sun et al (169) revealed that mitochondrial transplantation improved mitochondrial dynamics and respiratory function, reduced ROS production and effectively mitigated DIC. Notably, compared with the study by Maleki et al (167), the study by Sun et al (169) included a larger number of sources of mitochondria, including mouse heart, mouse and human arterial blood and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and all of them have a similar role in cardioprotection. Mitochondria isolated from hiPSC-CMs were injected intramyocardially into the mouse hearts and fluorescence imaging confirmed that exogenous mitochondria persisted in the mouse heart for at least 1 week. Mitochondrial transplantation promoted endogenous mitochondrial biogenesis and improved cardiac function (170). These findings suggest that mitochondrial transplantation enhances cardiac energy metabolism, reduces oxidative stress and promotes mitochondrial health, making it a powerful tool for alleviating DIC. Notably, mitochondria have a wide range of sources and choosing a suitable source is worth considering. Secondly, there is still a long way to go before mitochondrial transplantation therapy is used clinically, including safety and efficacy.

In conclusion, both exercise training, mitochondrial transplantation and intermittent fasting show promising potential as non-pharmacological strategies in alleviating and preventing DIC (Table II). While current studies provide strong support for the efficacy of these interventions, additional clinical trials and basic research are required to clarify their mechanisms, optimal implementation and synergistic effects with other therapies. A deeper understanding of these non-pharmacological interventions will contribute to safer and more effective treatment options for patients with cancer. The therapeutic strategies for DIC discussed here are presented in Fig. 5.