Introduction

Doxorubicin (DOX), an FDA-approved chemotherapy drug, is used to treat various types of cancers, including breast cancer and leukemia [1]. DOX can cause serious and potentially life-threatening side effects, such as cardiotoxicity [1]. The mechanisms involved in DOX-induced cardiac damage are complex and not yet fully understood [2], however, it is thought that may be caused by several factors, including reactive oxygen species (ROS) generation, mitochondrial dysfunction, calcium homeostasis disruption, and activation of apoptotic pathways [1, 3]. One of the mechanisms underlying the treatment with DOX is cardiac metabolism disruption [4]. DOX alters the expression of genes implicated in cardiac metabolism, which can impair cardiac function [5].

The mammalian target of rapamycin (mTOR) is a key regulator of cardiac energy metabolism by regulating fatty acid metabolism, glucose uptake and glycolysis, and mitochondrial function [6]. DOX has been shown induce cardiac dysfunction by the dysregulation of mTOR signaling [7]. It has also been suggested that DOX induces cardiac metabolism dysfunction in an mTOR-dependent manner [7, 8]. Recent research has proposed that the mTOR pathway could be a potential target for reducing the cardiotoxic effects of DOX [8, 9].

Several natural compounds (NCs) have been revealed to improve cardiac function in animal models of DOX-induced cardiotoxicity [10]. Some NCs can regulate mTOR expression, which may contribute to their cardioprotective effects against DOX treatment [11, 12]. The present study provides a review of the protective effects of NCs against DOX-induced cardiac injury, with a focus on their regulation of mTOR signaling pathways.

DOX-dependent Change in Cardiac Metabolism

The function and contraction of cardiomyocytes are sustained by oxidative phosphorylation of adenosine diphosphate (ADP) and the production of adenosine triphosphate (ATP) [5]. Mitochondria is responsible for supplying over 95% of the ATP molecules; the remaining 5% comes from the glycolysis process and the citric acid cycle [13]. Most of cardiac ATP (approximately 70%) is derived from fatty acids β-oxidation [14]. Glycolysis, a glucose metabolic pathway, produces a small amount of cardiac ATP. Ketone bodies, lactate, and amino acids contribute less to cardiac ATP generation in comparison with fatty acids and glucose [14]. Creatine phosphate (PCr) is a reservoir of high-energy phosphates in the myocardium to recycle ATP from ADP [15]. Therefore, the PCr/ATP ratio reflects the myocardial energy status [15]. Due to the continuous contractility, the myocardium consumes a high rate of ATP and depletes phosphate storage within a few seconds [14]. Since the cardiac function is dependent on mitochondrial ATP production, therefore ATP generation deficiency can alter myocardial contractility [14].

The cardiac metabolic change during DOX treatment has been reported that represents a compensatory response to imbalances in ATP demand and supply [16, 17]. DOX has been suggested that disrupt mitochondrial respiration and fatty acid oxidation in cardiomyocytes [18]. The mitochondrial accumulation of DOX is following its binding to cardiolipin located in the inner mitochondrial membrane [19]. The electron transport chain (ETC) is disrupted after DOX accumulation into the mitochondria and repressing mitochondrial complexes I and II [19]. ETC dysfunction is lead to decreasing in the cardiac ATP/ADP ratio and an increase in ROS generation, which damages the heart tissue [20]. DOX also affects glucose, amino acids, and fatty acids metabolism in the heart, resulting in decreased ATP production and cardiac dysfunction [4].

The overproduction of ROS in cardiomyocytes caused by DOX can have an impact on the metabolism of purine and pyrimidine nucleotides [21, 22]. This can occur through direct modifications to the nucleotides, inducing changes in DNA bases, activating DNA repair pathways, altering the availability of nucleotides, and influencing signaling pathways related to nucleotide metabolism [21]. As a result of the DNA damage, the metabolites of purine and pyrimidine can disrupt normal cardiac metabolism in various ways [21]. For example, they can affect the availability of nucleotides and interfere with the function of crucial enzymes involved in energy production [21, 22]. Additionally, DOX can affect the balance between pro-apoptotic BCL-2-associated X protein (BAX ) and anti-apoptotic B-cell lymphoma 2 (BCL-2) proteins, leading to structural modification of these proteins. BAX promotes cell death, while BCL-2 inhibits apoptosis [23]. The altered conformation of BCL-2 and BAX proteins caused by DOX can disrupt the normal regulation of apoptosis and have significant consequences on cardiac metabolism, including mitochondrial dysfunction, alterations in energy metabolism, and changes in nutrient utilization [21, 23].

mTOR-regulated Cardiac Metabolism

The mTOR is a protein kinase that phosphorylates the serine or threonine residues on cell proteins [24]. Phosphorylation is one of the primary mechanisms for regulating protein activity in signal transduction pathways [25]. The mTOR plays an essential role in regulating cardiac metabolism, cardiomyocyte growth, and survival [26]. Glycolysis is a metabolic pathway that generates ATP by converting glucose into pyruvate [27]. The mTOR activation promotes glycolysis by enhancing the expression and activity of key glycolytic enzymes, increasing the expression of glucose transporters, and facilitating glucose uptake into the heart cells [27, 28]. Lipid metabolism is another critical energy source in the heart, as it relies on the oxidation of fatty acids to generate ATP [27]. The mTOR regulates lipid metabolism by suppressing fatty acid synthesis and promoting fatty acid oxidation [27, 28]. The mTOR is the major component of two multiprotein complexes, mTOR complex 1 (mTORC1) and mTORC2 [24]. Each complex possesses distinct subunits that play a role in their specific functions [29] as depicted in Fig. 1. The regulatory-associated protein of mTOR (Raptor) plays a crucial role in the mTORC1 complex as its core component [29]. It is responsible for the cellular localization of mTORC1 and the recruitment of substrates [29, 30]. Additionally, Raptor is involved in conferring sensitivity of mTORC1 to rapamycin, a drug that inhibits its activity [29]. The core component of mTORC2 includes the stress-activated map kinase-interacting protein 1 (Sin1) and the rapamycin-insensitive companion of mTOR (Rictor) [29]. Sin1 plays a vital role in preserving the integrity of mTORC2 and facilitating the binding of substrates [30]. Rictor is responsible for conferring rapamycin insensitivity to mTORC2 [30]. Both complexes, mTORC1 and mTORC2, have two subunits in common: mTOR and the mammalian lethal with SEC13 protein 8 (mLST8) [30]. The mLST8 plays a critical role in stabilizing the mTOR kinase domain [30]. Moreover, the DEP domain-containing mTOR-interacting protein (Deptor) binds to both mTORC1 and mTORC2, acting as an endogenous inhibitor for both complexes [29, 30].

Fig. 1
figure 1

The subunits of mTORC1 and mTORC2 complexes

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Deptor, DEP domain-containing mTOR-interacting protein; mLST8, mammalian lethal with SEC13 protein 8; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; Raptor, regulatory-associated protein of mTOR; Rictor, rapamycin-insensitive companion of mTOR; Sin1, stress-activated map kinase-interacting protein 1.

The mTORC1 is mainly localized in the cytoplasm [31]. The activation of mTORC1 is regulated by levels of nutrients (amino acids, glucose, and fatty acids), growth factors, and hormones [6]. During nutrient-rich conditions, the lysosomal recruitment of mTORC1 by Ras-related GTP binding proteins (Rags) is the well-characterized mode of its activation [32]. Activated mTORC1 phosphorylates and inactivates the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, and causes its binding to 14-3-3 protein at the lysosome surface [33]. However, the inactivation of mTORC1 under starvation conditions leads to the TFEB/14-3-3 complex dissociation and rapid transport of TFEB to the nucleus for regulating the expression of autophagosomal and lysosomal genes [34]. Therefore, TFEB regulation by mTORC1 provides a mechanism for coordinating lysosomal biogenesis and autophagy with the availability of nutrients within the cell [31]. During autophagy, damaged proteins or organelles are delivered to the lysosome via the autophagosomes, a double-membrane vesicle, for degradation and maintaining cellular homeostasis [35].

The main upstream regulators of mTORC1 activity are the protein kinase AKT and the adenosine monophosphate–activated protein kinase (AMPK) [36, 37]. AKT phosphorylates and inactivates the tuberous sclerosis complex 2 (TSC2), a mTORC1 negative regulator, leading to mTORC1 activation [37]. AMPK conserves cellular energy by the inhibition of mTORC1 during low energy states [36].

The mTORC2 is activated by growth factors, insulin, and cellular stress signals [38]. It is localized in both the cytoplasm and the cytoplasmic membrane and regulates a variety of cellular processes, including metabolism and cell survival [39]. The mTORC2 is known as a critical regulator of AKT and protein kinase C (PKC) [39]. AKT and PKC signaling modulates glucose and lipid metabolism through the phosphorylation of metabolic enzymes or control of various transcription factors [39, 40]. AMPK and sirtuin 1 (SIRT1) can reduce mTORC2 activity by regulating upstream signaling pathways [39, 41].

Overall, the mTOR protein plays a significant role in heart metabolism by regulating metabolism of fatty acid and the intake and use of glucose [6]. It functions as a cellular sensor, coordinating the cellular response to changes in nutrient availability [29]. When there is an abundance of nutrients, the mTOR signaling is activated, promoting anabolic processes such as protein synthesis and suppressing catabolic processes such as autophagy [29]. mTORC1 mainly promotes cell growth by enhancing protein synthesis [30]. It regulates glucose uptake glycolysis, and fatty acid synthesis, thereby providing energy to cells in the form of ATP [30]. By regulating these processes, mTORC1 ensures that the heart has the necessary energy to function properly [6]. mTORC2 regulates the glucose transporter proteins, which are responsible for carrying glucose into cells [30]. By controlling the activity of these transporters, mTORC2 can influence the amount of glucose that enters cells and is available for energy production [29]. Additionally, mTORC2 is implicated in the regulation of fatty acid oxidation, the process by which fatty acids are broken down to generate energy [29].

Myocardial ischemia, or energy stress in the heart, can lead to the inhibition of mTORC1 and trigger protective adaptations, such as autophagy, which help limit myocardial infarction [42]. It has been suggested that mTORC1 has different roles during ischemia and reperfusion [42, 43]. During ischemia-reperfusion injury, mTORC1 activation promotes a metabolic shift from fatty acid oxidation to glycolysis by the upregulation of glucose transporters and increasing glucose uptake into the myocardium [42]. This increased glucose availability favors glycolysis, which is a more efficient energy-generating pathway during reperfusion. mTORC1 activation also can inhibit the activity of key enzymes involved in fatty acid oxidation [42]. Inhibition of these enzymes shifts the metabolism away from fatty acid oxidation and towards glycolysis [42, 43]. Dysregulation of mTOR signaling pathways has been implicated in a variety of diseases, including metabolic and cardiovascular diseases [6, 44].

Targeting mTOR by Natural Compounds in the DOX-induced Cardiotoxicity

Numerous studies have shown the effects of DOX on cardiac mTOR expression [7, 8, 45]. Some studies have shown that DOX induces mTOR expression in cardiomyocytes, while others have reported a decrease in mTOR expression [45,46,47]. It has been suggested that the dysregulated mTOR expression may be involved in the development of DOX-induced cardiotoxicity [48]. Studies have explored how NCs can protect against DOX-induced cardiac injury by modulating the mTOR pathway [12, 47, 49] (Table 1).

Table 1 Targeting mTOR by natural compounds in the DOX-induced cardiotoxicity
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The AKT/mTOR Pathway

Apigenin (API) is a flavonoid obtained from parsley, celery, and vine spinach [50]. It has various health benefits, including anti-inflammatory, antioxidant, antiviral, and anticancer effects [50]. API has been found to have cardioprotective properties, reducing blood pressure and the risk of atherosclerosis [51]. A study on mice investigated the potential protective effect of API against the cardiotoxic of DOX [52]. It was observed that API prevented DOX-induced apoptosis and autophagy, possibly through the activation of the AKT/mTOR pathway [52].

Curcumin (CUR) is a natural compound found in the turmeric (Curcuma longa L.) [53]. It possesses antitumor, antidiabetic, antihyperglycemic, antioxidant, and neuroprotective properties [54,55,56]. CUR has shown positive effects on cardiovascular health [56,57,58] and therapeutic efficacy against DOX-induced cardiomyopathy [49]. CUR reversed the down-regulation of AKT and mTORC1 caused by DOX in mice hearts and activated the AKT/mTOR signaling [49].

Luteolin-7-O-glucoside (LUTG) is a flavonoid found in Dracocephalum tanguticum Maxim [59]. It has various biological activities, such as anti-diabetic, anti-inflammatory, and anticancer effects [60,61,62]. LUTG has shown a potential protective effect in a cardiac hypertrophy model and protected against DOX-induced cardiotoxicity by down-regulating the AKT/mTOR pathway [63].

Neferine (NEF) is an alkaloid isolated from Nelumbo nucifera [64]. It possesses anti-diabetic, anti-cancer, and anti-microbial effects [65]. NEF has been reported to have potential therapeutic benefits for cardiovascular conditions, including atherosclerosis, hypertension, and heart failure [64, 66, 67]. NEF has shown a protective role in DOX-induced cardiotoxicity by inhibiting cardiac autophagy and increasing the expression of AKT and mTOR, thereby activating the AKT/mTOR pathway [68].

Wheat phenolics, such as ferulic acid (FA) and apigenin (AP) are natural compounds found in wheat and other cereal grains [69]. These phenolics have various biological activities, including antioxidant and anti-inflammatory effects [69, 70]. In a study investigating the potential protective effects against DOX-induced cardiotoxicity, the expressions of PI3K, p-AKT, and p-mTOR were found to be up-regulated in DOX-exposed cardiomyocytes treated with FA, AP, or whole wheat grain polyphenolic extract (WWGPE) [71]. The study suggests that WWGPE exhibited more effective cardioprotective effects compared to FA and AP, possibly due to the synergic interaction between the compounds [71]. These finding indicate that the protective effects of these wheat phenolics may be mediated through the activation of the PI3K/AKT/mTOR signaling pathway [71].

The mTOR/TFEB Pathway

Corosolic acid (CRA) is a natural triterpenoid isolated from the leaves of the banaba tree (Lagerstroemia speciosa) [72]. It possesses several health benefits such as anti-inflammatory, antioxidant, antidiabetic, and anticancer properties [72]. Studies have shown that CRA can reduce cardiac fibrosis in mice with heart failure and acute myocardial injury in diabetic rats [73, 74]. A study investigated the potential of CRA in improving myocardial injury caused by DOX [75]. It was found that CRA improved cardiac metabolism, ATP generation, and mitochondrial function [75]. It also increased the expression of AMPK and TFEB while reducing the expression of mTORC1 [75]. The study suggested that the cardioprotective effect of CRA against DOX-induced cardiotoxicity is related to the AMPK/mTORC1/TFEB pathway activation [75].

Dihydrotanshinone I (DHT) is a terpenoid compound derived from Salvia miltiorrhiza [76]. It has potential therapeutic effects in the treatment of cardiovascular diseases and cancer [76, 77]. In a study on DOX-induced cardiotoxicity, DHT was found to suppress the activation and nuclear localization of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [78], a transcription factor involved in the expression of inflammatory cytokines [79]. It also increased the nuclear expression of TFEB and decreased the cardiac ratio of p-mTOR/mTOR [78]. However, these effects were reversed by an mTOR agonist [78]. Therefore, the inhibition of mTOR expression by DHT may play a role in preventing DOX-related cardiac inflammation [78].

Tanshinone IIA (Tan-IIA) is the main lipophilic component extracted from Salvia miltiorrhiza [80]. Tan-IIA has anti-inflammatory, anti-oxidant, and immunomodulatory activities [81]. The cardiovascular pharmacology of Tan-IIA is characterized by its vasodilatory effect, antiarrhythmic effect, and inhibition of ischemia-reperfusion injury [82,83,84]. In a study on DOX-induced cardiotoxicity, Tan-IIA was found to restore the dynamic balance of autophagosome/autolysosome [85]. It reduced autolysosome accumulation and increased autophagosome formation, thereby promoting autophagy [85]. Tan-IIA up-regulated the expression of autophagy markers, including Beclin1 and the lysosomal-associated membrane proteins-1 (LAMP1), while decreasing the p-mTOR expression and increasing the TFEB expression [85]. These findings suggest that Tan-IIA protects against DOX-mediated cardiac damage by promoting autophagy through the inhibition of the mTOR/TFEB signaling pathway [85].

The AMPK/mTOR Pathway

Aspalathin (ASP), the primary polyphenol isolated from the rooibos plant (Aspalathus linearis), has various beneficial properties, antioxidant, anti-inflammatory, antidiabetic, antithrombotic, and anticancer effects [86, 87]. It has been shown to improve cardiovascular complications associated with diabetes [86]. In a study by Johnson et al. ASP prevented the decrease in cardiac ATP activity caused by DOX treatment [9]. While DOX treatment resulted in a slight increase in the p-mTOR/ t-mTOR ratio, Asp did not revered this effect [9]. Instead, ASP increased the expression of p-AMPK and autophagy in cardiomyocytes treated by DOX [9]. These findings suggest that the cardioprotective effects of ASP may not be mediated through the mTOR pathway [9].

Astragalus polysaccharide (APS) is derived from the roots of Astragalus membranaceus [88]. It exerts various pharmacological effects, including antidiabetic, anti-aging, antitumor, antibacterial, and antiviral properties [89]. ASP has shown a wide range of therapeutic effects in experimental cardiomyopathy, including cardiotoxicity caused by DOX and hypertrophic myocardium induced by isoproterenol [90, 91]. In a study on DOX-treated mice hearts, APS promoted mTOR activation and normalized autophagic flux [46]. The AMPK/mTOR pathway is considered one of the main targets of APS in protecting against DOX-induced impaired cardiac autophagy [46].

Dihydromyricetin (DHM) is a flavonoid found in the leaves of the Ampelopsis grossedentata [92]. It exhibits antioxidant, anti-inflammatory, mitochondrial dysfunction improvement, and autophagy regulation properties [93, 94]. Many benefits of DHM on the cardiovascular system have been reported [95]. In a study by Li et al. DHM pretreatment normalized left ventricular dysfunction in mice with DOX-induced cardiac injury [12]. DHM reversed DOX-induced inhibition of AMPK and induction of mTOR expression, suggesting that the cardioprotective effect of DHM involves activating the AMPK/mTOR pathway [12].

Scutellarin (SCU) is a polyphenolic flavonoid derived from Erigeron breviscapus [96]. It has antioxidant, anti-inflammatory, antiapoptotic, and neuroprotective properties [97, 98]. It has shown potential therapeutic benefits for cardiovascular diseases, such as heart failure and myocardial ischemia/reperfusion injury [96,97,98]. In rats with DOX-induced chronic cardiotoxicity, SCU treatment decreased AMPK expression and increased mTOR expression, preventing autophagy [99]. In another study, SCU reduced autophagy by increasing the expression of p-AKT and p-mTOR in cardiomyocytes treated by DOX [100]. SCU could potentially be a therapeutic option for preventing DOX-induced cardiotoxicity by inhibiting the AMPK/mTOR and the AKT-mTOR pathways [99, 100].

Thymoquinone (TQ) is a bioactive compound found in the seeds of Nigella sativa [101]. TQ has different pharmacological effects, such as antimicrobial, antihistamine, anti-inflammatory, antioxidant, and anticancer activities [102]. It has shown potential in preventing and treatment of myocardial ischemia/reperfusion injury and diabetic cardiomyopathy [101, 103]. TQ was found to have protective effects against DOX-induced cardiotoxicity in cardiomyocytes by decreasing the p-mTOR expression and increasing the p-AMPK expression [104]. This suggests that TQ induces cardiac autophagy through up-regulating the AMPK/mTOR pathway [104].

Glycyrrhizin (GL) is a glycoside derived from the Glycyrrhiza glabra root [105]. Many therapeutic activities of GL are determined, such as cardioprotective, neuroprotective, and hepatoprotective activities [106,107,108]. The protective effects of GL have been revealed in diabetic cardiomyopathy and isoproterenol-induced cardiac damage [109, 110]. LV et al. have revealed GL therapeutic strategy against DOX-induced cardiomyopathy [11]. Previous research have indicated that the high-mobility group box 1 (HMGB1) inhibitors down-regulated the AKT/mTOR pathway [111, 112]. GL is known as a direct HMGB1 antagonist [113]. In DOX-treated H9c2 cells, GL decreased the expressions of AKT, mTOR, and HMGB1 [11]. It also reduced the expressions of autophagy markers, including the protein light chain 3 (LC3) II and p62, and improved autophagy flux [11]. Overall, GL attenuated DOX-mediated cardiac autophagy by the down-regulation of the HMGB1-dependent AKT/mTOR pathway [11].

Resveratrol (RSV) is a polyphenol derived from grapes, berries, and peanuts [114]. It has anti-inflammatory, antioxidant, anti-cancer, neuroprotective, and cardioprotective properties [114]. Numerous studies have indicated that RSV can protect against heart failure, ischemia-reperfusion injury [115, 116], and DOX-induced cardiotoxicity [117, 118]. RSV was found to enhance DOX-mediated cardiac autophagy by reducing mTORC1 and increasing the E2 promoter binding factor 1 (E2F1) expression [117]. E2F1 is a transcription factor that is involved in regulating the expression of genes related to autophagy [119]. The up-regulation of the E2F1/mTORC1 pathway appears to contribute to the protective effect of RSV against cardiotoxicity [117]. Another study found that RSV activates AMPK, inhibits mTOR, and stimulates autophagy through the ULK1 complex [118]. ULK1 is a protein kinase involved in the process of autophagy and is stimulated by AMPK [120]. This suggests that RSV increases autophagy in cardiomyocytes via the activation of the AMPK/mTOR/ULK1 pathway [118].

Beta-LAPachone (β-LAP), a quinone-containing compound, is extracted from the lapacho tree [121]. It has antioxidant, anti-inflammatory, anti-obesity, anticancer, antiviral, antimicrobial, nephroprotective, neuroprotective, and cardioprotective effects [121,122,123]. The potential of β-LAP to prevent DOX-mediated cardiotoxicity has been investigated [47]. β-LAP has been found to reduce histopathological injury and improve the cardiac function [47]. SIRT1 is a main energy sensor that requires the nicotinamide adenine dinucleotide (NAD+) as a substrate [124]. Therefore, the intracellular level of NAD+ regulates SIRT1 function [124]. β-LAP increased the cardiac NAD+/NADH ratio and up-regulated SIRT1 expression in DOX-exposed heart tissues [47]. Increased SIRT1 expression and activity is associated with the deacetylation of the liver kinase B1 (LKB1) [125], level of autophagy marker LKB1 was elevated in the heart tissues of mice treated with β-LAP [47]. LKB1, as a kinase, activates AMPK through its phosphorylation [126]. β-LAP up-regulated AMPK expression and down-regulated the cardiac expression of mTOR [47]. These findings suggested that β-LAP up-regulated the LKB1/AMPK/mTOR pathway [47].

Spinacetin (SP) is a flavonoid found in spinach (Spinacia oleracea L.) [127]. There are various health benefits associated with the consumption of SP, including cardiovascular protection, antiasthmatic properties, hypoglycemic activity, and anti-inflammatory effects [128, 129]. In the context of DOX-induced myocardiopathy, SP treatment increased the expression of AMPK and SIRT3, while decreasing mTOR expression [127]. SIRT3 is a deacetylase localized to the mitochondria, which plays a role in phospho-activation of AMPK and acts as a positive regulator of autophagy [130]. This led to the induction of autophagy in cardiomyocytes, suggesting that SP alleviates DOX-triggered cardiotoxicity by up-regulating the SIRT3/AMPK/mTOR pathway [127].

Conclusion

The regulation of the mTOR pathway is complex, and the effects of NCs on this pathway seem to differ depending on the stage of DOX-mediated cardiotoxicity progression. DOX may impact mTOR signaling in dissimilar ways depending on the stage of cardiotoxicity. According to findings, the AKT/mTOR and AMPK/mTOR signaling have been implicated in the protective effects of NCs against DOX-changed cardiac metabolism. Figure 2 effectively represents the protective effects of NCs against DOX-induced cardiotoxicity by targeting the mTOR pathways. In general, the use of NCs to modify mTOR signaling shows promise as a strategy to reduce the harmful effects of DOX on the heart in clinical settings. However, thorough clinical trials are necessary to establish the right dosages, treatment duration, and potential interactions with other medications. Nevertheless, further research is needed to gain a complete understanding of the safety and effectiveness of these compounds before they can be widely utilized in clinical practice.

Fig. 2
figure 2

The protective effects of natural compounds against DOX-induced cardiac metabolism dysfunction by targeting the AKT/mTOR and AMPK/mTOR pathways. AMPK, adenosine monophosphate–activated protein kinase; ATP, adenosine triphosphate; BAX, BCL-2-associated X protein; BCL-2, B-cell lymphoma 2; DOX, doxorubicin; LKB1, liver kinase B1; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinases; ROS, reactive oxygen species; TFEB, transcription factor EB; TSC2, tuberous sclerosis complex 2; ULK1, Unc-51-like kinase 1

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