The Effects and Mechanisms of Indole Derivatives in Improving Doxorubicin-Induced Cardiomyopathy Free

Doxorubicin (DOX) is a chemotherapeutic agent that has been in clinical use since the 1960s and remains a first-line treatment for cancer. Unfortunately, the cardiotoxicity induced by DOX severely limits its long-term use [1]. DOX causes myocardial dysfunction, manifesting as congestive heart failure, left ventricular dysfunction, acute myocarditis, and arrhythmias, which can persist even years after chemotherapy is discontinued [2]. Clinical studies indicate that the incidence of DOX-induced cardiomyopathy (DIC) is dose-dependent. The incidence is 5.0% at a cumulative dose of 400 mg/m², 26.0% at 550 mg/m², and 48.0% at 700 mg/m² [3]. DOX-induced cardiotoxicity significantly affects chemotherapy adherence, quality of life, and survival in cancer patients. Currently, the only drug approved for the treatment of DIC, dexrazoxane, carries the risk of reducing the antitumor efficacy of DOX and increasing the risk of secondary malignancies [4]. The FDA has restricted the use of dexrazoxane to metastatic breast cancer patients receiving more than 300 mg/m² of DOX [5].

Indole derivatives are a class of natural and synthetic compounds with broad biological activities, characterized by a core structure consisting of a fused benzene ring and a pyrrole ring, forming the indole ring system [6]. These compounds are widely found in various plants, microorganisms, and human metabolic products, playing an important role, especially in the secondary metabolites of plants [7]. Indole compounds not only exhibit antimicrobial and antioxidant properties in plant defense mechanisms but also display a variety of pharmacological effects in mammals, including anti-inflammatory, antioxidant, anticancer, neuroprotective, and cardioprotective effects [8, 9]. Moreover, indole derivatives show promising potential in regulating mitochondrial function, inhibiting apoptosis, and improving oxidative stress, particularly in the prevention and treatment of cardiovascular diseases [10, 11]. The mechanisms of action of these compounds have attracted significant attention. Due to their diverse biological activities, indole compounds are considered to be a class of therapeutically promising drug candidates, especially in the field of myocardial protection, where they hold promise as effective candidates for the intervention of DIC.

Oxidative stress is a key mechanism in the pathogenesis of DIC. In normal physiological conditions, a homeostatic balance is maintained between oxygen-free radicals and antioxidants [12]. However, excessive oxygen-free radicals can damage proteins, nucleic acids, membrane structures, and other cellular components [13]. The major endogenous antioxidant systems primarily include the thioredoxin (TRX) system [13], glutathione (GSH) system, and superoxide dismutase (SOD) system. Among these, the reducing equivalents provided by Trx2 and thioredoxin reductase-2 (TRXR2) via NADPH can reduce reactive oxygen species (HO•) to H₂O. In our previous review, we also discussed the interplay between the TRX system and other antioxidant systems [14]: The TRX system, together with the glutathione-glutaredoxin system, controls the redox environment of mammalian cells. Furthermore, the mammalian TRX system and GSH system can cross-provide electrons and serve as backup systems for each other.

During its metabolism, DOX generates a large amount of reactive oxygen species (ROS), including superoxide anions, hydrogen peroxide, and others, which attack lipids, proteins, and DNA in cardiomyocytes, leading to structural and functional damage. Specifically, DOX interacts with the electron transport chain in mitochondria through its quinone ring structure, generating superoxide anions, which, via the Fenton reaction, further produce the highly reactive hydroxyl radicals [15, 16]. These ROS trigger lipid peroxidation in cardiomyocytes, damaging the cell membrane, increasing its permeability, and ultimately leading to cell apoptosis or necrosis [17]. Furthermore, oxidative stress also impairs the antioxidant defense system within the cell. Under normal conditions, antioxidant enzymes in cardiomyocytes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX), are capable of eliminating ROS and effectively counteracting oxidative stress. However, DOX significantly inhibits the activity of these enzymes, further exacerbating the accumulation of oxidative stress [18]. This series of oxidative damages, especially in metabolically demanding cardiomyocytes, accelerates the decline in cell function, resulting in cardiac dysfunction and eventually progressing to DIC.

The mechanism of oxidative stress extends beyond direct ROS production and involves the activation of various signaling pathways. For example, an excess of ROS can activate the nuclear factor-κB (NF-κB) signaling pathway, leading to the upregulation of pro-inflammatory factors, which further exacerbate myocardial inflammation and injury [19, 20]. Additionally, oxidative stress can activate mitochondrial pathways that trigger apoptosis, thereby resulting in continuous loss of cardiomyocytes [21].

In the pathogenesis of DIC, the inflammatory response is a critical pathological event following oxidative stress. In addition to inducing oxidative stress in myocardial tissue, DOX also triggers immune system activation, leading to the release of pro-inflammatory cytokines, which exacerbate myocardial cell injury [22].

DOX-induced inflammation is closely related to the NF-κB signaling pathway. NF-κB is a key transcription factor that regulates the expression of various inflammation-related genes [23]. Under the influence of DOX, oxidative stress and DNA damage activate IκB kinase (IKK), causing the phosphorylation and degradation of IκB proteins, thereby releasing NF-κB from its inhibitory state. Activated NF-κB translocates to the nucleus and induces the expression of pro-inflammatory genes, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), which amplify and sustain the inflammatory response [24, 25]. Moreover, DOX can enhance the inflammatory response by activating the inflammasome, a protein complex responsible for sensing inflammation within cells. Activation of the inflammasome leads to the activation of caspase-1, triggering the release of TNF-α and IL-1β, which further intensify cardiac inflammatory damage [26].

These pro-inflammatory cytokines not only act directly on cardiomyocytes but also attract additional immune cells to infiltrate myocardial tissue, further amplifying the local inflammatory response. The inflammatory mediators and oxidative products released by immune cells, such as peroxides and nitric oxide, exacerbate cardiomyocyte apoptosis and necrosis, leading to structural damage and functional loss of the myocardium [27, 28]. Furthermore, the prolonged activation of inflammatory cells and sustained inflammation can result in fibrosis, contributing to cardiac remodeling and ultimately leading to heart failure [29].

The inflammatory response not only directly aggravates myocardial damage but also interacts with oxidative stress, creating a vicious cycle. The excessive release of pro-inflammatory cytokines increases the generation of ROS, which in turn promotes the expression of inflammatory factors, further amplifying inflammatory injury [30, 31]. Therefore, controlling the inflammatory response, particularly by inhibiting the NF-κB signaling pathway and reducing the release of pro-inflammatory cytokines, is a crucial therapeutic strategy for alleviating DIC.

DOX has an affinity for mitochondria and can bind to cardiolipin on the inner mitochondrial membrane, disrupting the function of the electron transport chain [32, 33]. This property of DOX inhibits the activity of the electron transport chain complexes, leading to the generation of excessive reactive oxygen species (ROS) within cardiomyocytes, which can directly damage the mitochondrial membrane and mitochondrial DNA (mtDNA), further causing mitochondrial dysfunction [34, 35]. As the heart is an energy-intensive organ and mitochondria are the primary source of cellular energy, the integrity and function of mitochondrial membranes are crucial for normal myocardial metabolism and physiological function. When mitochondrial membranes are damaged by DOX, the membrane potential is lost, electron transport chain function is impaired, and ATP production is reduced, resulting in insufficient energy supply for the cell [36]. This energy metabolic disturbance exacerbates myocardial cell apoptosis and necrosis.

Additionally, mitochondrial damage exacerbates cardiomyocyte death by activating various apoptotic pathways. DOX-induced ROS not only directly affect the mitochondrial membrane, causing the release of cytochrome c from mitochondria into the cytoplasm but also upregulate the Bax/Bcl-2 ratio, activating the mitochondrial-mediated intrinsic apoptosis pathway [37]. Furthermore, Ca²⁺ overload within mitochondria is another significant feature of DOX-induced cardiomyopathy. Excessive Ca²⁺ accumulation leads to the opening of the mitochondrial permeability transition pore, resulting in mitochondrial membrane depolarization and triggering cell death pathways [38, 39].

Finally, DOX also significantly impacts mitochondrial quality control, primarily through the excessive activation of mitochondrial fission. When cells experience oxidative stress, mitochondrial fission is activated to increase mitochondrial numbers, which allows cells to clear damaged mitochondria through division. However, when oxidative stress is severe or prolonged, mitochondrial fission cannot effectively counteract the stress, leading to impaired mitochondrial function [40]. Imbalance between mitochondrial fission and fusion due to oxidative stress is one of the key mechanisms in DOX-induced cardiomyopathy. Several studies have shown that DOX intervention leads to downregulation of mitochondrial fusion proteins, including mitofusin 1 and 2 (MFN1 and MFN2) and optic atrophy-1 (OPA1), while mitochondrial fission protein dynamin-related protein 1 (DRP1) is upregulated, resulting in excessive mitochondrial fission [41]. In the hearts of DOX-treated mice, increased expression of p-DRP1 triggers mitochondrial fission [42], and Drp1 knockout has been shown to alleviate DOX-induced cardiotoxicity [41]. Therefore, inhibiting excessive mitochondrial fission is a potential therapeutic target for intervention in DOX-induced cardiomyopathy.

The occurrence of apoptosis is a complex and highly regulated multistep process. DOX-induced myocardial apoptosis is closely associated with mitochondrial damage and oxidative stress [43]. When oxidative stress or intracellular calcium ion concentrations become abnormal, it leads to increased mitochondrial membrane permeability and a decline in mitochondrial membrane potential. The increased permeability of the mitochondrial outer membrane results in the release of cytochrome c into the cytoplasm, where it binds to the apoptosis protease-activating factor 1 (Apaf-1) and ATP to form the apoptosome. This, in turn, activates caspase-9 within the apoptosome, which further activates downstream caspase-3, ultimately triggering apoptosis [1]. The Bcl-2 family of proteins plays a crucial regulatory role in this process. Proapoptotic proteins such as Bax and Bak promote the increase in mitochondrial membrane permeability, while antiapoptotic proteins such as Bcl-2 and Bcl-XL inhibit this process. Oxidative stress can influence the Bax/Bcl-2 ratio, thereby promoting or inhibiting apoptosis [44, 45]. Furthermore, studies have shown that DOX induces myocardial cell apoptosis by enhancing p53 expression, lowering GATA-4 levels, and promoting p300 degradation, while also activating heat shock factors such as HSF-1 and HSP25 to further regulate p53 expression [46‒48]. Additionally, DOX can activate signaling pathways such as MAPK, p38, and Jun N-terminal kinase (JNK), leading to the cleavage of Bcl-2 family proteins and caspases-3 and -9. This process is accompanied by calcium homeostasis disruption and mitochondrial damage, and it increases the expression of death receptors, such as TNFR1 and Fas, thereby further amplifying the apoptotic process [49‒51].

Ferroptosis is a novel form of programmed cell death characterized by the excessive accumulation of intracellular iron and the generation of lipid peroxides, ultimately leading to cell membrane rupture and cell death [52]. Unlike traditional apoptosis and necrosis, ferroptosis exhibits unique morphological, and molecular features. It is typically initiated by intracellular iron ions, leading to the oxidation of cell membrane lipids and the formation of lipid peroxides [52]. Numerous studies have shown that iron plays a role in DOX-induced cardiotoxicity, particularly in cases of intracellular iron overload. It has been reported that increased iron intake via the transferrin receptor, along with an imbalance in intracellular ferritin and mitochondrial iron regulation, contributes to DOX-induced cell damage. In contrast, inhibiting the transferrin receptor significantly alleviates cell injury [53]. As the only FDA-approved protective agent for DOX-induced cardiotoxicity, dexrazoxane exerts part of its protective effect by chelating intracellular free iron, thereby reducing iron-mediated oxidative stress [54]. Moreover, the ATP-binding cassette (ABC) transporter ABCB8 can alleviate DOX-induced myocardial injury by decreasing mitochondrial iron loading and reducing ROS generation [55]. Importantly, research indicates that the use of apoptosis inhibitors significantly reduces DOX-induced cell death but does not have a significant impact on lipid peroxidation, suggesting that ferroptosis and apoptosis may be relatively independent processes in DOX toxicity [56].

The endoplasmic reticulum (ER) is a critical organelle in cardiac myocytes, primarily responsible for protein folding, processing, and calcium storage and balance. Under normal conditions, the ER folds and modifies newly synthesized proteins to ensure their proper structure and function [57]. However, under conditions of oxidative stress, calcium homeostasis imbalance, hypoxia, or exposure to toxic substances (such as DOX), the ER environment in cardiac myocytes is disturbed, leading to the accumulation of unfolded or misfolded proteins [58]. This imbalance activates the unfolded protein response (UPR), triggering ER stress [59].

Under the action of DOX, unfolded or misfolded proteins accumulate in the ER of cardiac myocytes, thereby activating the UPR and initiating ER stress signaling pathways. These pathways include IRE1α, PERK, and ATF6, which respond to ER stress through distinct mechanisms [60]. However, when ER stress becomes prolonged and UPR signaling cannot restore balance, destructive responses such as apoptosis, autophagy, and inflammation gradually dominate, ultimately leading to cell damage and cardiotoxicity. Specifically, the IRE1α pathway not only regulates protein folding but also interacts with c-JNK to activate the expression of proapoptotic factors, such as BAX and BAD, thus inducing apoptosis in cardiac myocytes [61]. The PERK pathway inhibits the protein synthesis factor eIF2α, reducing the production of newly synthesized proteins while inducing the expression of apoptosis-related proteins such as CHOP (C/EBP homologous protein), further exacerbating apoptosis [62, 63]. The ATF6 pathway regulates cell survival by enhancing the expression of stress-related genes; however, prolonged activation can also intensify apoptosis [64]. In addition to activating these pathways to induce apoptosis, DOX also promotes calcium homeostasis imbalance and increases oxidative stress during the ER stress process, which in turn triggers more autophagy and inflammation [60, 65].

Indole derivatives are a class of structurally diverse organic compounds that are widely distributed in nature and exhibit significant biological activity in drug development [66] (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000546061). The basic structure of indole derivatives consists of an indole ring, a bicyclic structure that imparts unique chemical properties and biological activities [67]. Indole derivatives have a broad range of applications in the pharmaceutical field, including antitumor, antibacterial, anti-inflammatory, and antiviral activities [68].

In recent years, increasing research has highlighted the potential application of indole derivatives in the treatment of cardiovascular diseases. For instance, certain indole derivatives, such as melatonin, have been shown to exert protective effects on cardiac cells by regulating oxidative stress, inflammation, and apoptosis [69]. Additionally, indole compounds have been found to improve cardiac function by influencing mitochondrial function and metabolic status in cardiomyocytes, thereby playing a positive role in the treatment of heart failure and cardiomyopathies [70]. Furthermore, indole derivatives are also considered as specific biomarkers for predicting disease prognosis [71]. Overall, indole derivatives have wide-ranging regulatory effects on the body, making them an important area of potential in the design of novel therapeutic agents.

Indole derivatives exhibit significant antioxidant effects that help mitigate oxidative damage induced by DOX. For example, indole-3-carbinol (I3C) can reduce ROS generation by activating the Nrf2 signaling pathway. Nrf2 is crucial in the antioxidant stress response, and during DOX-induced oxidative damage, I3C promotes the nuclear translocation of Nrf2, thereby enhancing the expression of antioxidant enzymes such as HO-1 and NQO1, which strengthens the cell’s antioxidant defense [72]. Additionally, melatonin, an important indole derivative, significantly alleviates oxidative stress, necroptosis, and apoptosis induced by DOX through the modulation of the Sirt1/Nrf2 pathway, thus protecting myocardial tissue [73].

Moreover, indole derivatives are widely found in various natural plants, making indole-rich foods potential candidates for mitigating DOX toxicity. Studies have shown that diets rich in di-indolylmethane (DIM) can enhance the expression of antioxidant enzymes, thereby boosting myocardial antioxidant defense and reducing the side effects of DOX treatment [74]. These findings suggest that indole derivatives hold significant potential in combating DOX-induced oxidative stress and cardiotoxicity, offering new antioxidant therapeutic strategies for patients.

The mechanisms underlying the antioxidant effects of indole derivatives are also worth exploring. First, indole compounds can directly scavenge free radicals, including ROS and reactive nitrogen species. Their unique structure endows them with strong electron transfer capabilities, enabling them to reduce oxidative stress in cells by capturing free radicals [75, 76]. Furthermore, multiple studies have shown that indole derivatives regulate mitochondrial fission and fusion, which is critical for mitochondrial quality control and helps reduce mitochondrial-derived oxidative stress [77]. Additionally, the activation of antioxidant enzymes is another mechanism through which indole derivatives exert their antioxidant effects. This is primarily achieved by activating Nrf2 and promoting the expression of downstream molecules such as NQO1 and HO-1 [72]. Under physiological conditions, Nrf2 is bound to Keap1 in the cytoplasm, whereas under stress conditions, Nrf2 dissociates from Keap1 and translocates into the nucleus to activate downstream antioxidant molecules. Our team has previously conducted in-depth research on the mechanism by which indole derivatives activate Nrf2: in a DIC mouse model, intervention with indole-3-lactic acid (ILA) downregulated Keap1 levels, thereby promoting Nrf2 nuclear translocation and activating the expression of downstream antioxidant molecules such as NQO1, HO1, and SOD [78]. Consistently, we observed the same phenomenon in mice treated with indole-3-propionic acid (IPA) [79]. Furthermore, we investigated the potential pathways through which ILA exerts this effect, revealing that the aryl hydrocarbon receptor, a receptor for indole derivatives, serves as a critical link between indole derivatives and Nrf2 activation [78]. In summary, indole derivatives combat oxidative stress in cardiomyocytes through multiple pathways.

Mitochondrial damage is one of the central mechanisms underlying DOX-induced cardiotoxicity. DOX induces structural and functional changes in mitochondria, leading to disturbances in cellular energy metabolism, loss of membrane potential, excessive fission, and apoptosis [80]. Indole derivatives exhibit unique advantages in protecting mitochondrial function and can effectively mitigate the damage caused by DOX in cardiac tissue. IPA, a gut metabolite, has been shown to inhibit DOX-induced excessive mitochondrial fission in cardiomyocytes, thereby protecting heart function. This effect is primarily associated with its regulation of mitochondrial dynamics proteins such as p-DRP1 and MFN1 [81]. Additionally, melatonin, another significant mitochondrial protectant, maintains mitochondrial homeostasis and bioenergetics by activating the AMPK/PGC1α signaling pathway. Specifically, melatonin enhances mitochondrial biogenesis by upregulating the expression of PGC1α, NRF1, and TFAM, thereby reducing oxidative damage to mitochondria [82]. Moreover, studies have found that melatonin regulates the YAP signaling pathway, inhibiting DOX-induced mitochondrial ferroptosis, reducing lipid peroxidation and apoptosis, and significantly improving DOX-induced myocardial dysfunction [83]. These results suggest that indole derivatives protect mitochondrial function through multiple pathways, making them a potential strategy for preventing DOX-induced cardiotoxicity and offering new possibilities for improving heart health in cancer patients.

Mechanistically, mitochondrial dysfunction and oxidative stress exhibit a mutually reinforcing and interdependent relationship [84, 85]. When mitochondrial function is compromised or the electron transport chain becomes dysfunctional, ROS production is significantly elevated, thereby triggering oxidative stress [86]. Notably, oxidative stress is not merely a consequence but also a contributing cause of mitochondrial dysfunction. Excessive ROS triggers lipid peroxidation of mitochondrial membranes, protein oxidation, and DNA damage, thereby disrupting mitochondrial structure and function. The mitochondrial protective effects of indole derivatives are closely linked to their antioxidant properties. Numerous studies have demonstrated that these compounds simultaneously mitigate oxidative stress and alleviate mitochondrial injury [82, 87].

Inflammation plays a crucial role in the initiation and progression of DOX-induced cardiomyopathy, and it is closely linked to pathological processes such as oxidative stress. Indoles exert significant protective effects in DOX-induced myocardial injury by inhibiting necroptosis and modulating inflammatory responses. Melatonin, for instance, activates the Sirt1/Nrf2 pathway to reduce oxidative stress and necroptosis, while simultaneously downregulating the expression of pro-inflammatory mediators, including TNF-α and IL-6, thereby significantly inhibiting the inflammatory response [73]. Additionally, I3C activates the Nrf2/ARE signaling pathway, upregulating the expression of antioxidant enzymes such as HO-1 and NQO1, and suppressing the NF-κB pathway to reduce the expression of iNOS and COX-2, effectively alleviating DOX-induced myocardial inflammation and oxidative damage [72].

Another indole derivative, DIM, also exhibits anti-inflammatory effects. It inhibits the nuclear translocation of NF-κB, thereby reducing the production of inflammatory factors like TNF-α and IL-6, which suppresses myocardial inflammation and mitigates myocardial damage [74]. Furthermore, the modulation of the gut microbiota, such as through fecal microbiota transplantation, can also influence inflammation and metabolite generation by regulating the Nrf2 pathway, thereby improving DOX-induced myocardial injury [83]. This suggests that indole derivatives may play a key role in these processes.

In summary, indole derivatives regulate multiple inflammatory pathways, inhibit pro-inflammatory mediators, and suppress inflammation, offering an effective protective strategy against DOX-induced myocardial injury. This highlights their potential for clinical application in cardiotoxicity prevention.

The regulatory effects of indole derivatives on ferroptosis have gained attention in recent research. DIC is often accompanied by oxidative stress and ferroptosis, leading to myocardial cell injury. Studies have shown that melatonin (Mel), a potent mitochondrial antioxidant, exhibits significant protective effects in modulating ferroptosis. In DOX-induced cardiomyocyte models, Mel reverses the process of apoptosis, mitochondrial lipid peroxidation, and ferroptosis by regulating the expression of Yes-associated protein (YAP), thereby alleviating myocardial damage [83]. Moreover, Mel inhibits ferroptosis by upregulating the antioxidant protein GPX4 and downregulating the expression of ACSL4, reflecting its role in regulating oxidative stress and maintaining cellular iron homeostasis [83].

Beyond DOX-induced cardiomyopathy, Mel also suppresses ferroptosis in other disease models through activation of various signaling pathways. For instance, in a non-alcoholic fatty liver disease model, Mel alleviates endoplasmic ER stress via the MT2/cAMP/PKA/IRE1 signaling pathway, thereby inhibiting ferroptosis [88]. In a sepsis-induced acute kidney injury (SAKI) model, Mel reduces ferroptosis by upregulating the Nrf2/HO-1 signaling pathway [89]. Furthermore, in an ultraviolet-induced cataract model, Mel inhibits ferroptosis through the SIRT6/p-Nrf2/GPX4 and SIRT6/NCOA4/FTH1 pathways, thereby delaying cataract formation [90]. Collectively, these studies suggest that indole derivatives can regulate ferroptosis through the inhibition of oxidative stress, ER stress, and modulation of antioxidant pathways, thereby demonstrating promising myocardial protective effects.

Apoptosis is a critical pathological process in DOX-induced cardiac injury, making the inhibition of apoptosis essential for protecting cardiac function. Among indole derivatives, melatonin plays a significant role in reducing cardiomyocyte apoptosis through the Sirt1/Nrf2 pathway [73]. Another study demonstrated that the regulation of DOX-induced cardiomyocyte apoptosis by melatonin is also related to the YAP gene [83]. Additionally, I3C reduces DOX-induced apoptosis by upregulating the antiapoptotic protein Bcl-2 and downregulating the expression of Bax and caspase-3 [72]. Previous research by our team has reported a direct and close relationship between gut microbiota dysbiosis and DIC [91]. Recent studies indicate that the apocynum venetum leaf extract modulates the gut microbiota, and further investigation into its mechanism revealed that apocynum venetum leaf extract significantly increased the levels of indole-3-IPA and acetic acid. Both IPA and acetic acid reduced the levels of BNP, CK, and LDH in a DIC mouse model, with IPA improving DOX-induced cardiac injury by inhibiting apoptosis [92]. The natural alkaloid 3,3′-DIM significantly alleviates DOX-induced apoptosis by upregulating Bcl-2 expression and downregulating Bax and caspase-3 expression. Its antiapoptotic effects are closely associated with its antioxidant capacity, as it can reduce DNA damage in cells, which is crucial for mitigating apoptosis [11].

Indole derivatives play a crucial role in regulating ER stress and can alleviate cell damage associated with various diseases. Studies have shown that indole compounds such as melatonin, through their antioxidant, anti-inflammatory, and antiapoptotic properties, can effectively inhibit ER stress under different pathological conditions. Melatonin alleviates ER stress through the MT2/cAMP/PKA/IRE1 signaling pathway, demonstrating significant protective effects in a non-alcoholic fatty liver disease model [88]. Another indole derivative, IPA, inhibits ER stress in a Parkinson’s disease model, thereby protecting neuronal cells from death, and shows promising potential in neurodegenerative diseases [93]. These studies highlight the multifaceted mechanisms through which indole derivatives regulate ER stress, providing potential therapeutic strategies for diseases associated with ER stress.

Currently, dexrazoxane is the only clinically approved drug for treating DIC. However, its use has been reported to correlate with reduced antitumor efficacy of DOX and an increased risk of secondary malignancies [94, 95]. Our team has also published studies comparing the effects of dexrazoxane and indole derivatives in counteracting DOX-induced cardiotoxicity. We found that both dexrazoxane and ILA alleviated DIC, with no significant difference in cardiac functional recovery between the two treatments in mice [78]. Additionally, certain reducing active molecules, such as hydropersulfides (RSSH), have demonstrated promising potential in combating DIC. RSSH can mitigate oxidative stress by activating Nrf2 and, most importantly, enhance DOX’s antitumor efficacy in vitro [96].

Natural plants exhibit broad biological functions, including antioxidant and anti-aging effects [97, 98]. Indole derivatives are not only bioactive molecules widely present in various natural plants but also exist extensively in the human body as metabolites. They are primarily synthesized through the metabolic transformation of tryptophan by gut microbiota [99]. Thus, indole derivatives are not foreign substances to the human body. Numerous studies have shown that indole derivatives exhibit significant protective effects against DOX-induced cardiomyopathy. In this article, we have summarized the potential pathways and mechanisms through which indole derivatives protect against DOX-induced cardiomyopathy: (a) antioxidant effects, (b) protection of mitochondrial function, (c) anti-inflammatory effects, (d) inhibition of ferroptosis, (e) anti-apoptosis, and (f) protection against ER stress (shown in Fig. 1). These mechanisms collectively demonstrate the multifaceted protective effects of indole derivatives against DOX-induced cardiomyopathy (Table 1). Furthermore, since indole derivatives are predominantly found in natural plants and human metabolites, they exhibit favorable safety profiles. Some studies even suggest that indole derivatives may, to some extent, restore the sensitivity of drug-resistant cell lines to DOX, which is an intriguing finding [100]. Another study delved into the molecular mechanisms underlying this effect, revealing that indole-3-carbinol downregulates the expression of the antiapoptotic protein Bcl-2 in tumor tissue while upregulating Bax, cytochrome c, caspases, and other molecules, leading to PARP cleavage and tumor cell apoptosis, thus enhancing the effectiveness of DOX therapy [101]. These findings further suggest that indole derivatives are highly promising molecules with clinical application potential.

However, there are certain limitations to this review. Most of the existing studies focus on melatonin, while research on other indole derivatives, such as ILA, IPA, and others, is still limited. Our team has previously reported that the gut microbiota metabolite IPA regulates mitochondrial dynamics to protect against DIC [81]. Moving forward, our team plans to explore more indole derivatives and conduct further research into their molecular mechanisms of action, pharmacodynamics, and safety. We will focus on optimizing the structure of indole derivatives to enhance their efficacy and selectivity, and explore their effects at different doses and in combination therapies to improve their clinical applicability. Additionally, it is essential to investigate the potential applications of indole derivatives in other types of cardiomyopathies and related cardiovascular diseases to expand their therapeutic scope.

We deeply appreciate MD. Liping Meng for pointed advice and discussion for writing this article. Parts of the Figure 1 were drawn by using resources from Servier Medical Art (http://smart.servier.com/). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).

The authors declare that they have no competing interests.

This work was supported by Clinical Research Fund Project of Zhejiang Medical Association (First Batch) (2020ZYC-A61).

The first draft was written by Jing Sun, Fangfang Qian, and Fengmei Shi; the manuscript was revised by Oushan Tang and Yinhong Cheng; the illustrations were created by Haoliang Zhou; and Jiedong Zhou was responsible for overseeing and advancing the entire process.