Anthracycline drugs act by binding to DNA TOPs, inserting into DNA, promoting DNA strand breaks, and causing cardiac damage (Tewey et al., 1984). TOPs are enzymes that regulate DNA replication, transcription, recombination, and chromatin remodeling by inducing temporary single or double-strand breaks when they open DNA strands. In human cells, there are two Top2 isoforms, Top2α and Top 2β. Top2α is expressed at high levels during the cell cycle in undifferentiated and proliferating cells, including those of tumors, with varying levels. In contrast, Top2β is expressed in quiescent and differentiated cells, such as those found in cardiac muscle, maintaining consistent levels throughout the cell cycle (Wang, 2002) (Figure 2).

DOX binds to Top2α, arresting tumor cells in the G₁/G₂ phase and inhibiting DNA replication, leading to apoptosis. However, anthracycline drugs also bind to Top2β, inhibiting DNA replication, resulting in apoptosis of cardiac muscle cells. Experiments have shown that specific knockout of the Top2β gene in mouse hearts can alleviate DOX-induced heart failure. Compared to the control group, double-strand DNA breaks decrease, suppressing apoptosis (Zhang et al., 2012). DZR besides its iron-chelating function, can inhibit Top2β activity, which may contribute to its cardiac protection (Vavrova et al., 2013). Crystal structure analysis shows that DZR stabilizes ATP in the ATPase domain of Top2β, preventing the reopening of the Top2β subunit and locking the Top2β monomer in a closed dimeric structure. This, in turn, prevents anthracycline drugs from binding to the TOP-DNA complex and inducing DNA damage. (Classen et al., 2003; Lee et al., 2017). Researchers have developed anthracycline compounds that specifically target Top2α. While this approach does not affect the expression of Top2β in differentiated cardiac muscle cells, it may potentially impact undifferentiated cardiac progenitor cells expressing Top2α.

In addition to expressing Top2β, cardiac muscle cells also express mitochondrial TOP 1 (Top1mt), which regulates the stability of mtDNA. Mice that lack Top1mt demonstrate mitochondrial defects, such as compromised synthesis of respiratory proteins and disrupted mitochondrial ultrastructure. They are more susceptible to DOX-induced damage compared to normal mice, leading to cardiac injury (Khiati et al., 2014). Therefore, Top1mt has a cardioprotective role, and genetic variations in Top1mt may increase sensitivity to anthracycline cardiotoxicity.

Under normal physiological conditions, there is only a minimal amount of biologically active free iron in cardiac muscle cells. Most iron ions are bound to iron proteins to prevent their escape and avoid tissue and cell damage. When there is an excess of iron ions in the cells, anthracycline drugs increase intracellular reactive oxygen species (ROS) and induce oxidative stress reactions, causing cardiac muscle damage (Xu et al., 2005).

When a significant amount of anthracycline drugs accumulates within cells, the anthracycline drug’s core structure, anthraquinone, can be reduced to semiquinone radicals by reduced nicotinamide adenine dinucleotide phosphate dehydrogenase (NADPH). Nucleotide phosphate dehydrogenase (NADPH) to semiquinone radicals. These radicals undergo auto-oxidation under aerobic conditions, generating anthraquinone radicals and superoxide anions (O^2-), leading to intracellular O^2- accumulation. Meanwhile, O^2- is converted to hydrogen peroxide (H₂O₂) by superoxide dismutase (SOD). H₂O₂ can react with iron ions through the Fenton reaction, converting H₂O₂ into toxic hydroxyl radicals (-OH), thus causing sustained increases in intracellular ROS levels and oxidative stress reactions, leading to cardiac muscle damage (Doroshow and Davies, 1986; Winterbourn, 1995).

Anthracycline drugs can also directly interact with iron ions, forming complexes in a cyclic manner between Fe²⁺ and Fe³⁺, leading to oxidative stress and mitochondrial dysfunction (Myers et al., 1982). DOX derivatives can also chelate iron ions from cytoplasmic iron-regulatory protein 1 (IRP1) iron-sulfur (Fe-S) clusters, rendering IRP1 inactive. Inactive IRP1 increases the synthesis of transferrin receptor (TF), reducing the synthesis of intracellular iron storage protein (ferritin), disrupting cellular iron homeostasis, ultimately resulting in continued increases in intracellular free iron (Minotti et al., 1998) (Figure 3).

Mitochondrial iron export protein (ATP Binding Cassette Transporter B8, ABCB8) is one of the essential factors affecting mitochondrial iron metabolism during DOX treatment. Studies have reported that DOX can downregulate the expression of ABCB8, leading to increased iron accumulation within mitochondria. Transgenic mice overexpressing ABCB8 exhibit protective effects against DOX-induced cardiac muscle damage. ABCB8 overexpression reduces the iron content in mitochondria, thereby reducing DOX-induced cardiac toxicity (Menon and Kim, 2022). This suggests that reducing intracellular mitochondrial iron ion content may be an effective strategy to prevent anthracycline-induced cardiac toxicity.

Although both in vitro and in vivo studies confirm an increase in free iron content within cardiac muscle cells after anthracycline treatment, the role of iron disturbance in inducing cardiac damage is still debated. Not all iron chelators have shown efficacy in mitigating anthracycline-induced cardiac damage (Stěrba et al., 2013). DZR, an iron chelator, can reduce anthracycline-induced cardiac damage, but other potent iron chelators, such as deferoxamine, deferiprone, and deferasirox, have yet to show this protective effect (Sultan et al., 2017).

As the primary site for cellular energy production and aerobic respiration, mitochondria are primarily composed of the mitochondrial outer membrane, intermembrane space, mitochondrial inner membrane, and mitochondrial matrix (Varga et al., 2015). In addition to their roles in energy conversion, the tricarboxylic acid cycle, oxidative phosphorylation, and calcium storage (Nunes-Nesi et al., 2013), mitochondria also play significant roles in processes such as cell proliferation, metabolism, and apoptosis (Su et al., 2023). An increasing body of research suggests that anthracycline drugs induce cardiac damage associated with mitochondrial dysfunction. When anthracycline drugs enter cardiac muscle cells, they alter mitochondrial membrane permeability, causing the release of cytochrome c (Cyt c) into the cytoplasm, subsequently triggering apoptosis. Additionally, anthracycline drugs can inhibit the activity of mitochondrial inner transcription enzymes, leading to ongoing oxidative stress in damaged mitochondria and exacerbating apoptosis (Parker et al., 2001) (Figure 4).

Anthracycline drugs’ cardiac damage is related to muscle fiber degradation and disruption (Sawyer et al., 2002). In vertebrate skeletal muscle fibers, Titin plays a crucial role in the generation and stability of sarcomeres, serving as the assembling framework for muscle fibers (Granzier and Labeit, 2004). Calpain, a type of protease, can cause the degradation of Titin (Lim et al., 2004). When anthracycline drugs induce cardiac damage, it leads to the overexpression of Calpain within cardiac muscle cells, causing muscle fiber disruption and necrosis (Ali et al., 2010). Storr and others have demonstrated that endogenous inhibitor of Calpain, Calpastatin, can alleviate anthracycline drug-induced cardiac toxicity (Storr et al., 2011). It’s worth noting that Titin degradation is an early process of cardiac cell damage triggered by DOX (Lim et al., 2004). Previous research has found Titin fragments in the urine of anthracycline-treated patients, which holds diagnostic significance for cardiac injury, reflecting potential myocardial damage (Tanihata et al., 2019) or skeletal muscle damage (Misaka et al., 2019). Therefore, Titin fragments can serve as a biomarker for detecting early anthracycline-induced cardiac damage.

Treatment with anthracycline drugs can cause an imbalance in intracellular sarcoplasmic reticulum calcium homeostasis (Sala et al., 2020). In normal cardiac muscle cells, Ca²⁺ is mainly stored in the mitochondria, sarcoplasmic reticulum, and sarcolemma, playing a vital role in maintaining the excitation-contraction coupling of cardiac muscle cells. Anthracycline drugs can disrupt the membrane’s permeability, activate Ca²⁺ channels in the sarcoplasmic reticulum, increase the release of Ca²⁺ from the sarcoplasmic reticulum to the cytoplasm, rapidly increase intracellular free Ca²⁺ concentration, affecting cardiac electrical activity, resulting in various arrhythmias, known as sarcoplasmic reticulum calcium overload. During anthracycline drug treatment, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) causes changes in the calcium signaling pathway-related genes (Luo et al., 2013). Impaired calcium homeostasis leads to the generation of intracellular reactive ROS, and anthracycline drugs reduce sodium and calcium exchange in the sarcolemma (Caroni et al., 1981). This calcium overload results in mitochondrial damage, aggravated oxidative stress, structural damage, and cell apoptosis. Anthracycline drugs can also inhibit the gene expression of Ca²⁺-ATPase on the sarcolemma of cardiac muscle cells, affecting the biosynthesis of Ca²⁺-ATPase, reducing its activity, reducing the sarcolemma’s Ca²⁺ uptake capability, leading to reduced ATP production in mitochondria, disrupting cardiac energy metabolism, worsening cell damage, and even causing cardiac cell death.

Anthracycline drugs can also activate cardiac matrix metalloproteinase 2 (MMP2) (Chan et al., 2018). In normal cardiac muscle cells, MMP2 is present in the sarcomeres and the cell cytoskeleton. When oxidative stress occurs, MMP2 is activated and responsible for degrading specific proteins, including Troponin I (TNI) (Wang et al., 2002), Myosin Light Chain 1 (MYL1) (Sawicki et al., 2005), α-Actinin (Sung et al., 2007), and Titin (Ali et al., 2010). Therefore, transgenic mice overexpressing MMP2 show reduced muscle contractile function, sarcomere disruption, and myosin protein hydrolysis (Bergman et al., 2007). In anthracycline drug-induced cardiac toxicity models, the increase in MMP2 levels and activity is a primary cause of early intracellular Titin protein hydrolysis and extracellular matrix remodeling (Chan et al., 2021). These adverse reactions can be prevented by oral MMP2 inhibitors, demonstrating the potential benefits of MMP2 inhibitors in preventing anthracycline-induced cardiac toxicity (Chan et al., 2021).

Mitochondria are the primary targets of anthracycline drugs’ actions. Cardiac muscle cells are rich in mitochondria, with 35%–40% more mitochondria compared to other cells, making them susceptible to damage (Goffart et al., 2004). In normal signal transduction processes, low levels of ROS are generated to maintain intracellular signaling, but under many pathological conditions, ROS levels increase from low to high (Liou and Storz, 2010; Peoples et al., 2019; Songbo et al., 2019). When anthracycline drugs enter cardiac muscle cells, they generate a significant amount of ROS by Generation of large amounts of ROS by reducing redox cycling in electron transport chain complex I, leading to ATP synthesis impairment (Davies et al., 1983). After the substantial ROS generation within mitochondria, anthracycline drugs transform into semiquinone radicals. Semiquinone radicals readily react with oxygen to generate O^2-, which can react with SOD to produce H₂O₂. Simultaneously, anthracycline drugs also produce a substantial amount of iron ions within cardiac muscle cells. Iron ions, serving as the electron donors for H₂O₂ in the Fenton reaction, lead to the generation of -OH, sustaining ROS production (Canzoneri and Oyelere, 2008). Generated ROS react with mitochondrial lipids, proteins, and nucleic acids, disrupting mitochondrial functions, including protein translation, expression, and inducing lipid peroxidation, generating a substantial amount of malondialdehyde (MDA). MDA is one of the major products of membrane lipid peroxidation, and its content is often used to indicate the degree of cellular membrane lipid peroxidation. Studies have found that if intracellular ROS levels continuously increase, it can worsen cellular membrane lipid peroxidation, leading to an increase in MDA content (Liu et al., 2018). Therefore, MDA content can also indirectly reflect the extent of myocardial damage (Eder and Arriaga, 2006). SOD is a metalloenzyme that plays a crucial role in the oxidative and antioxidative balance of the body, It catalyzes the disproportionation of O^2- to oxygen and hydrogen peroxide. (Henning et al., 2022).SOD can intercept the pathways of ROS-induced cell damage, timely repairing cell damage caused by ROS. As the primary scavenger of ROS within mitochondria, SOD plays an essential role in maintaining mitochondrial ROS levels and the stability of the mitochondrial environment (Bauer et al., 2014). In experiments on DOX-induced primary cardiac cell damage, DOX was found to increase intracellular MDA levels and reduce SOD activity, resulting in oxidative stress in cardiac cells (Dhingra et al., 2020). Wang et al. research showed that THP increased ROS levels in H9c2 cells and significantly elevated MDA content in rat serum while reducing SOD activity. RUT can reverse the oxidative stress damage caused by THP (Wang et al., 2018). In an experiment conducted by Aleixo and others on DOX-induced cardiac damage in rats, it was found that SOD activity decreased, MDA content increased in the cardiac tissues of model group rats compared to normal group rats, leading to the accumulation of a large amount of lipid peroxidation products in cardiac tissues, causing severe oxidative stress reactions (Marques-Aleixo et al., 2016) (Figure 5).

Research has also found that Nrf2, as a basic leucine zipper bZIP protein, can mitigate cell damage caused by ROS and electrophiles by regulating the expression of antioxidant proteins, keeping cells in a stable state, maintaining the dynamic balance of redox in the body, and counteracting oxidative damage. Nrf2 deficiency can exacerbate cardiac toxicity and cardiac dysfunction. In Nrf2 gene knockout (Nrf2^−/−) mice, the adverse reactions of DOX cause cardiac muscle cell necrosis and cardiac dysfunction, which are related to oxidative stress, impaired autophagy, and increased accumulation of polyubiquitin aggregates (Li et al., 2014).

In the normal physiological state, the cardiomyocyte is a terminally differentiated, non-proliferative mature cell. Therefore, apoptosis of cardiac myocytes plays a crucial role in the cardiotoxicity induced by anthracyclines. Recent studies have confirmed that anthracycline drugs can induce apoptosis in cardiac myocytes, thereby damaging the myocardium. The primary pathway of anthracycline-induced cell apoptosis is mitochondria-mediated intrinsic signaling. When anthracycline drugs enter cardiac myocytes, they cause the release of Cyt c from the mitochondrial inner membrane, which then binds to Apaf-1 to form the apoptosome. The apoptosome activates the caspase family, leading to cell apoptosis. AKT, as a key factor in the apoptosis signaling pathway, can inhibit cell apoptosis by regulating the Bcl-2 family. In addition to the mitochondria-mediated intrinsic signaling pathway, anthracycline drugs can also induce programmed necrosis and cell pyroptosis, resulting in damage to cardiac myocytes (Figure 6).

Dexrazoxane is a substance that binds to iron and decreases the levels of reactive oxygen species. It has been proven to be a successful agent in protecting the heart in patients who are at a high risk and are receiving anthracycline therapy (Reichardt et al., 2018). The primary antitumor mechanisms of anthracyclines include inhibition of Top2, which leads to double-stranded DNA breaks, mitochondrial dysfunction, and increased ROS production (Bures et al., 2017). However, these mechanisms also lead to cardiomyocyte damage, which increases the risk of cardiotoxicity. The United States Food and Drug Administration (FDA) has implemented stringent guidelines to address the heart toxicity caused by dexrazoxane. These guidelines restrict the use of dexrazoxane to women with advanced metastatic breast cancer who have been treated with a minimum of 300 mg/m² of doxorubicin or 540 mg/m² of epirubicin (Swain et al., 1997; Ganatra et al., 2019). This is mainly because the use of dexrazoxane may increase the risk of infection, decrease the rate of anticancer response, and elevate the risk of secondary malignancies (Swain et al., 1997).

The cardioprotective effects of dexrazoxane are currently thought to include inhibition of DOX-Top2 complex formation, thereby preventing deleterious cardiomyocyte apoptosis (Bures et al., 2017). In addition, in a recent study, Yu et al. demonstrated that dexrazoxane was able to effectively ameliorate DOX-induced inflammation and necrosis by inhibiting the NF-kB and p38 MAPK pathways (Yu et al., 2020). Although the cardioprotective effect and clinical application of dexrazoxane still need to be further evaluated, it is currently believed that its protective mechanisms include cellular iron chelation, attenuation of cardiomyocyte apoptosis, iron apoptosis and necrosis (Swain et al., 1997; Bures et al., 2017; Reichardt et al., 2018; Yu et al., 2020). Therefore, as an adjuvant to anthracycline therapy, dexrazoxane has potential clinical value in high-risk patients, and its efficacy and safety need to be further verified in future studies.

The use of β-blockers as prophylaxis prevents the development of systolic heart failure in female patients with breast cancer treated with anthracyclines (Kalay et al., 2006; Kaya et al., 2013; Nabati et al., 2017; Abuosa et al., 2018). Recently, Zhang et al. demonstrated through in vitro and in vivo studies that the β-blocker carvedilol (Carvedilol) attenuates DOX-induced inflammation, oxidative stress, and activation of pro-apoptotic pathways (Zhang et al., 2019). Specifically, carvedilol reduces the phosphorylation of the transcription factor nuclear factor-κB (NF-κB) (Zhang et al., 2019). Phosphorylation of NF-κB leads to its nuclear localization, which triggers the expression of pro-inflammatory cytokines, such as interleukin (IL) 1β, IL-18 and tumor necrosis factor-α (TNF-α) (Zhang et al., 2019). It was shown that carvedilol reduced the levels of phosphorylated NF-κB and its downstream inflammatory cytokines IL-1β, IL-18 and TNF-α in DOX-treated mice and cells (Zhang et al., 2019). Thus, β-blockers may exert cardioprotective effects by down-regulating inflammatory pathways.

In addition, DOX decreases NRF2, and carvedilol has been shown to partially reverse this decline (Zhang et al., 2019). Carvedilol reduced oxidative stress in DOX-treated mice by increasing the expression of NRF2 and its downstream genes, such as NQO1, HO1, and SOD1 (Zhang et al., 2019) Thus, carvedilol enhanced the antioxidant capacity of cardiomyocytes, enabling them to resist anthracycline-induced oxidative damage more effectively. In addition, β-blockers attenuate anthracycline-induced cardiomyocyte apoptosis (Spallarossa et al., 2004; Arozal et al., 2010; Zhang et al., 2019). Carvedilol was able to partially reverse the anthracycline-induced increase in pro-apoptotic protein Bax and activated caspases (Arozal et al., 2010; Zhang et al., 2019). Given that ROS production is the cause of BAX activation, it is theorized that the antioxidant properties of carvedilol may be linked to the decrease in cardiomyocyte apoptosis (Minotti et al., 2004) To summarize, β-blockers safeguard cardiomyocytes from anthracycline-induced cardiotoxicity by employing three mechanisms: inhibiting inflammation, boosting the antioxidant capacity of cardiomyocytes, and decreasing apoptosis.

Angiotensin-converting enzyme (ACE) inhibitors are believed to be beneficial because they help decrease the generation of ROS and boost the activity of scavenging free radicals. Both of these processes are often disrupted in anthracycline therapy (Hiona et al., 2011; Abd El-Aziz et al., 2001; Chopra et al., 1989; al-Harbi, 1993). Hydrogen peroxide is a ROS that can induce programmed cell death, known as apoptosis, in cardiomyocytes (Hiona et al., 2011). Research has demonstrated that the ACE inhibitor enalapril decreases the occurrence of electrons flowing out of sequence, perhaps leading to a reduction in the generation of ROS. This mechanism may contribute to enalapril’s ability to protect the heart (Hiona et al., 2011). In addition, previous studies have shown that ACE inhibitors such as enalapril and captopril may act as free radical scavengers (Abd El-Aziz et al., 2001; Chopra et al., 1989; al-Harbi, 1993). Although it was initially thought that ACE inhibitors required sulfhydryl groups in order to scavenge free radicals, later studies have shown that ACE inhibitors lacking sulfhydryl groups, such as enalapril, still have the ability to scavenge free radicals (Mira et al., 1994). Finally, it has been shown that both enalapril and captopril increase the activity of the endogenous antioxidant enzyme SOD (de Cavanagh et al., 1997). Altogether, these effects would enhance the antioxidant defenses of cardiomyocytes, thereby reducing their vulnerability to anthracycline-induced oxidative stress.

ACE inhibitors reduce the amount of circulating angiotensin II (Ang II), whereas angiotensin receptor blockers (ARBs) act by preventing Ang II from binding to the AT1 receptor (Saleem et al., 2010). Activation of the AT1 receptor is associated with the upregulation of extracellular signal-regulated protein kinases (ERKs), which stimulate cardiomyocyte hypertrophy (Akazawa et al., 2013). In addition, blockade of AT1 receptors with ARBs leads to Ang II stimulation of AT2 receptors, which is associated with some of its cardioprotective effects (Schmieder, 2005). For example, the ARB Valsartan has been shown to reduce the expression of inflammatory cytokines, including monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α, IL-6, and IL-1β (Schmieder, 2005). Thus, it may be postulated that the cardioprotective impact of ARBs is attributed to their capacity to inhibit cardiac remodeling and reduce inflammation linked to anthracycline-induced cardiotoxicity (Akazawa et al., 2013).

Statins, which are often referred to as HMG-CoA reductase inhibitors, are medications used largely to decrease cholesterol levels in individuals with atherosclerotic cardiovascular disease (Schachter, 2005). In the context of preventing anthracycline-induced cardiac insufficiency, RAS antagonists and β-blockers are frequently examined. However, a randomized controlled trial conducted by Nabati et al. (Nabati et al., 2019) revealed that statins have a protective effect in preventing chemotherapy-induced cardiotoxicity in breast cancer patients. Statins have little impact on hemodynamic indicators, specifically heart rate and blood pressure, making them potentially more manageable for people with these conditions.

Despite differences in the pharmacodynamics of the various statin drugs, they all reduce hepatocellular cholesterol synthesis by inhibiting HMG-CoA reductase, the rate-limiting step in the conversion of HMG-CoA to mevalonate (Schachter, 2005). Administration of statins reduces plasma concentrations of LDL, which causes atherosclerosis, while increasing concentrations of HDL, which has antioxidant, anti-inflammatory and antithrombotic effects (Henninger and Fritz, 2017). It has been suggested that statins exert their main effects by modulating Ras homolog (Rho) GTPase signaling (Henninger and Fritz, 2017). Studies have shown that Rho GTPase is able to reduce ROS levels by indirectly inhibiting the pro-oxidative NADPH system as well as modulating endothelial nitric oxide synthase (eNOS) (Schachter, 2005; Henninger and Fritz, 2017). In addition, in vitro studies have shown that cellular pretreatment with atorvastatin protects cardiomyocytes from DOX-induced apoptosis (Oh et al., 2020). DOX treatment activates the FOXO1 protein, which competitively inhibits the binding of STAT3 to Sp1 (Oh et al., 2020). The STAT3/Sp1 transcriptional complex is required for the expression of apoptosis inhibitory protein survivin (Oh et al., 2020). Pretreatment with statins is able to restore survivin in cardiomyocytes by inactivating FOXO1 through protein phosphorylation and inhibition of nuclear translocation (Oh et al., 2020). In addition to their cardioprotective effects, statins can sensitize tumor cells to certain chemotherapeutic agents while protecting cardiomyocytes, thereby increasing the anticancer response rate (Oh et al., 2020).

The role of microbial metabolites from food metabolism on the development of cardiometabolic diseases is now extensively acknowledged (Tremaroli and Bäckhed, 2012). The gut microbiota can function as an independent endocrine organ in the host body by secreting, degrading, or modifying chemicals through several metabolic pathways. These compounds have the ability to directly or indirectly impact organisms, which justifies the recognition of the gut microbiota as an endocrine organ. Short-chain fatty acids, such as acetic, propionic, and butyric acids, are key metabolites produced by the gut microbiota. These acids have been found to have significant impacts on heart function in animal models (Li et al., 2012).

The cardioprotective effect of butyric acid is mainly related to its epigenetic effect, as it is a potent inhibitor of histone deacetylase (HDAC), which is known to protect the heart from maladaptive hypertrophy and ischemic injury (Antos et al., 2003; Kong et al., 2006; Gallo et al., 2008; Granger et al., 2008). In addition, several studies by Raphaeli and colleagues revealed the dual activity of butyric acid and its precursor drugs, which on the one hand enhanced the antitumor activity of Dox in cancer models and on the other hand protected cardiomyocytes from Dox-induced cardiotoxicity (Rephaeli et al., 2007; Tarasenko et al., 2012; Moyal et al., 2018). Recently, the ability of in vivo oral administration of FBA, a new synthetic derivative of butyrate, to protect the heart from Dox cardiotoxicity and prevent mitochondrial dysfunction was demonstrated for the first time (Russo et al., 2019). Thus, the use of gut microbe-derived metabolites as nutritional supplements may represent a promising new approach for the treatment of Dox cardiotoxicity.

Exercise has been acknowledged as a developing treatment for anthracycline-related cardiotoxicity. Research conducted on rodents has demonstrated that exercise is a potent stimulus that protects the heart and mitigates the harmful effects of DOX. A recent comprehensive analysis of two preclinical investigations found that physical activity interventions, such as forced treadmill running or voluntary free-wheel running, can reduce the damage to heart contractile function caused by DOX-induced fractional shortening (FS) injury (Ghignatti et al., 2021; Naaktgeboren et al., 2021). Exercise enhances cardiac function irrespective of the timing of the training in relation to DOX therapy. However, exercise conducted before DOX treatment is typically more successful in preserving cardiac contractility (Ghignatti et al., 2021). It is worth mentioning that even a brief period of aerobic exercise, lasting only 5 days, or a single exercise session of 60 min, might offer substantial advantages in reducing heart harm caused by DOX (Wonders et al., 2008; Lien et al., 2015). These findings offer compelling evidence to support the use of short- and long-term exercise interventions in the treatment of anthracycline cardiotoxicity.

Marques-Aleixo et al. conducted a study to examine the impact of 12 weeks of aerobic exercise, either through forced or voluntary wheel running, on the levels of protein carbonylation and lipid peroxidation produced by DOX in male rats (Marques-Aleixo et al., 2015). Exercise performed alongside DOX treatment was discovered to have a substantial impact on reducing cardiac protein carbonylation and lowering mitochondrial MDA levels. Chicco et al. found that an 8-week exercise regimen involving voluntary wheel running led to a notable decrease in left ventricular MDA levels in female rats (Chicco et al., 2005). In male rats, a 3-week exercise regimen or a single exercise session prior to DOX treatment also resulted in reduced myocardial MDA levels (Wonders et al., 2008; Shirinbayan and Roshan, 2012). The results indicate that engaging in exercise either at the same time or before receiving DOX treatment effectively reduces the negative effects of DOX on protein carbonylation and lipid peroxidation.

Induced human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are particularly important in cardiovascular research because other methods typically require invasive biopsies of human cardiac tissue, which are not sustainable in long-term culture. HiPSC-CMS not only overcome these limitations, but also mimic the physiological properties of in vivo cardiomyocytes, expressing most heart-specific ion channels and currents, and have a functional contractile apparatus. By analyzing their action potential morphology via membrane clamp, these cells can be further classified into atrial, ventricular, and sinus node subtypes (Burridge et al., 2016).

However, there are some limitations to using hiPSC-CMS. For example, they are considered immature and are closer to fetal cardiomyocytes in terms of structure, electrophysiological properties, genetic program and metabolism. They are structurally disordered in the myotome and lack T-tubules (Cao et al., 2008; Lundy et al., 2013). Due to differences in the in vivo environment and in vitro culture conditions, it is difficult for these cells to fully mimic the properties of adult cardiomyocytes. These shortcomings may complicate the interpretation of drug responses and make it difficult to predict translational effects in mature cells.

A future application of hiPSC-CMs may be the prediction of cardiotoxicity, a concept initially demonstrated by Burridge et al. in a study involving breast cancer patients treated with DOX. Although much work remains to be done in the preclinical application of hiPSC-CMs, the preliminary results are encouraging and may ultimately change the way drug screening is done, making it applicable to both groups and individuals. Currently, approaches to mitigating toxicity consist primarily of identifying known risk factors and comorbidities, followed by regular screening of patients by echocardiography, electrocardiography, angiography, and serum biomarkers (Manrique et al., 2017). Zhang et al. found that transplantation of iPSC-MSCs into a mouse model of anthracycline-induced cardiomyopathy retained more mitochondria in cardiac tissues and preserved the bioenergetics of cardiac tissues compared with bone marrow (BM)-MSCs. Unlike primary cardiomyocytes, which have limited availability and short lifespan in culture, cardiomyocytes derived via hiPSC-CMs can be easily generated and maintained in vitro. Models employing hiPSC can bridge the gap between cellular studies and animal models and clinical experiments, thus contributing to physiologically relevant mechanistic and target identification studies (Zhang Y. et al., 2016). Yang et al. monitored mitosis in hiPSC-CMs using the mt-Keima probe. The results showed that there were differences in basal mitotic rates in differentiated hiPSC-CMs. This result showed that cardiac mitosis was highly sensitive to the chemotherapeutic drug doxorubicin and hypoxia-induced cardiac ischemic conditions (Yang et al., 2022).