Traditional Chinese Medicine Monomers Are Potential Candidate Drugs for Cancer-Induced Cardiac Cachexia

Cardiovascular diseases (CVDs) and malignant tumors constitute severe public health burdens in China and around the world. According to 2023 statistics of the World Health Organization (WHO), CVD is the leading cause of death worldwide, with 17.9 million deaths in 2019, accounting for 32% of global deaths, representing a major obstacle to sustainable human development [1]. Cancer ranks as the second leading cause of death after heart disease, with approximately 19.3 million new cases and nearly 10 million deaths worldwide in 2020, as reported by the Global Cancer Observatory [2]. Cardiac-oncology, an emerging interdisciplinary field, addresses the cardiovascular complications observed in cancer patients, which have increasingly become a critical aspect of patient prognosis and survival with advancements in diagnostic and treatment methods. This field mainly includes cardiovascular damage occurring during cancer development or antitumor therapies. The shared risk factors and prevention strategies for tumors and CVD underscore the close connection between these prevalent diseases [3, 4].

Cardiac cachexia, a relatively well-recognized syndrome in the context of CVD, especially in terminal chronic heart failure, manifests as decreased myocardial mass, changes in myocardial structure, and myocardial dysfunction. In oncological settings, patients consistently face an increased risk of cardiac events and injuries as a side effect of cancer treatments. Recent studies have shown that cancer can directly affect the heart in clinical scenarios, as individuals not receiving treatment exhibit features and symptoms of cardiac cachexia [3, 4]. Both preclinical and clinical evidence support the concept of cancer-induced cardiac cachexia (CICC). These data underscore the critical need for continued research into CICC and the development of new therapeutic strategies for managing both cancer and its cardiac complications.

The cardiac atrophy, cardiac fibrosis, and cardiac contractile dysfunction are three typical phenomena of CICC. Regardless of whether it involves xenograft tumors or primary tumors, both conditions are characterized by damaged and disordered myocardial morphology. Decreased heart wall thickness and decreased myocardial cell width result from a reduction in cardiomyocyte size in therapy-naïve patients and preclinical models [5]. This primarily manifests as a decrease in the number of myofibrils in the hearts of terminal cancer patients and preclinical models, which ultimately leads to a decrease in myocardial mass. A reduction in the number of cardiomyocytes may also lead to changes in myocardial morphology [6]. This phenomenon is termed cachexia-induced cardiac atrophy. Cardiac fibrosis is a pathological manifestation marked by abnormal proliferation of fibroblasts, excessive collagen deposition, and abnormal distribution, constituting another form of cardiac structure alteration [7]. Cardiac fibrosis is often associated with a systemic impact of tumor burden on the heart accompanied by impaired left ventricular ejection fraction (LVEF) [8]. In both isolated hearts and cardiomyocytes from xenograft tumor models or in vivo, left ventricular systolic and diastolic dysfunction prolongs the entire cardiac cycle, with markedly diminished systolic and slowed diastolic functions of cardiomyocytes, along with a decreased heart rate [6]. It has also been observed that the amplitude, upstroke rate, and decay rate of calcium transients are all decreased in cardiomyocytes from xenograft tumor models due to myocyte-intrinsic impaired calcium cycling [6]. In hearts from primary tumor models in vivo, reductions in left ventricular end-diastolic diameter (LVEDD), left posterior wall thickness, and left ventricular mass have been documented [9].

Proteolysis might be one of the possible mechanisms underlying cachexia-induced cardiac atrophy [10]. Additionally, excessive pro-inflammatory cytokines play a significant role in the development of CICC. Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) promote cardiac atrophy by inducing fetal genes and facilitating protein breakdown [10]. Nuclear factor-κB (NF-κB), a central downstream transcription factor of these cytokines, primarily acts through muscle ring finger 1 (MuRF1) to promote protein breakdown [10]. Consequently, anti-inflammatory treatments can be effective in reducing CICC-related cardiac atrophy. Tumors can lead to an increase in myocardial inflammatory cytokine levels, which in turn promote cardiac fibrosis by stimulating collagen deposition [6]. Studies on the role of inflammatory cytokines in cardiac fibrosis mainly focus on IL family members and TNF-α. In myocardial fibroblasts, IL-18 can induce excessive fibronectin synthesis and deposition through the overactivation of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway. High concentrations of TNF-α promote the synthesis of enzymes that further enhance transforming growth factor-β signaling, also via overactivation of the PI3K/Akt pathway [11]. TNF-α-induced cardiac fibrosis is associated with myocardial cell necrosis and apoptosis, stimulation of metalloproteinases, and reduced expression of metalloproteinase inhibitors mediated by NF-κB/transforming growth factor signaling [12]. IL-1β contributes to collagen deposition in the marginal regions of cardiac infarction. Additionally, an increased ratio of TNF-α/IL-10 (an anti-inflammatory cytokine) exacerbates cardiac fibrosis [13]. Consequently, anti-inflammatory strategies can be effective in reducing cardiac fibrosis in CICC. Cardiac dysfunction in CICC can arise from several factors: a calcium (Ca²⁺) imbalance due to the degradation of calcium-toolkit proteins, decreased sensitivity of myofilaments to Ca²⁺ following the degradation of myofilament proteins, and cardiac fibrosis. A reduction in phospholamban phosphorylation and a decreased activity of sodium/calcium exchangers contribute to left ventricular dysfunction in primary tumor models [9]. TNF-α not only promotes the degradation of crucial functional proteins but also directly reduces the sensitivity of myofilaments to Ca²⁺ [14]. Moreover, inflammatory cytokines impair heart function, and cardiac fibrosis compromises the diastolic function [6, 13]. Thus, anti-inflammatory interventions may help mitigate cardiac dysfunction in CICC.

Oxidative stress during cancer progression can induce apoptosis in cardiomyocytes through activation of the mitogen-activated protein kinase (p38 MAPK) pathway [10]. Additionally, oxidative processes can lead to calcium overload via protein modification [10]. Changes in myofilament proteins, including the predominant loss of myosin heavy chain, and increased levels of troponin-I (TnI) and troponin-T (TnT) are observed in CICC. Such alterations typically occur in xenograft tumor models [4]. Therefore, antioxidative treatments are vital therapeutic strategies to counteract CICC.

Disruptions in the Akt signaling pathway may cause cachexia-induced cardiac atrophy due to diminished protein synthesis when the PI3K/Akt/mTOR pathway is underactivated [4, 10]. In contrast, overactivation of this pathway may lead to pathological hypertrophy associated with fibrosis [11]. This complex dysregulation highlights the need for balanced activation of the PI3K/Akt pathway in cardiomyocytes to potentially safeguard against CICC.

Although no current effective and clinically approved treatment options or Food and Drug Administration (FDA)-approved drugs available for CICC, there are still regular pharmacological and nonpharmacological treatment strategies against CICC reported [8]. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, or diuretics have shown mixed results in patients suffering from CICC as previously reviewed [8]. Withaferin A (steroidal lactone), ACM-001 (anabolic-catabolic transforming agent), and Entinostat (histone deacetylase inhibitors) have shown promising results as emerging treatment strategies against CICC in preclinical models. Besides, improvement of appetite via medication (megestrol acetate), nutritional interventions (lauric acid and glucose), and aerobic endurance exercise or resistance exercise have shown benefits in the treatment of CICC [8].

Clinical observations have shown that terminal cancer patients frequently experience cardiac wasting and are prone to left ventricular mass loss. Current research on traditional Chinese medicine (TCM) monomers for treating cardiac injuries has become a prominent focus and is recognized as an effective adjunct therapy for prolonging the survival of these patients [15]. TCM, including herbs, formulas, and monomers, has attracted considerable attention as an alternative and potent modality for heart diseases [16]. TCM monomers, derived from Chinese herbs, are active compounds with defined molecular structures and are known for specific pharmacological actions, making them suitable for treating or preventing heart diseases [17]. Compared to conventional therapies, TCM monomers offer unique pharmacological properties, achieving comparable therapeutic effects with lower toxicity and fewer side effects due to their multitarget actions [18]. Research has demonstrated that certain TCM monomers improve cardiac morphology, structure and function through mechanisms involving anti-inflammation, antioxidation, and pro-survival in different heart disease models, making them promising candidates for treating CICC (Table 1).

Research has demonstrated the anti-inflammatory and antioxidative properties of Astragalus [19]. It could also strengthen cardiac contractility to protect against cardiac injury. Astragaloside IV, a principal active component, has been shown to enhance cardiac contractility and provide protection against cardiac injuries. In studies involving chronic heart failure in rats, Astragaloside IV significantly reduced collagen volume fraction compared with control groups [56, 57]. Moreover, it mitigated changes in LV end-diastolic volume, LV end-systolic volume, LV fractional shortening, and LVEF caused by inflammation. It also decreased the levels of cardiac troponin I and lactate dehydrogenase (LDH) and inhibited the expression of IL-1β, TNF-α, monocyte chemotactic protein 1, and IL-6 in a mouse model of lipopolysaccharide (LPS)-induced cardiac dysfunction. Astragaloside IV’s efficacy may stem from its ability to inhibit NF-κB and activate the PI3K/Akt pathway, thereby preventing ventricular remodeling [20]. It also alleviated the inflammatory infiltration in cardiomyocytes, diminished the levels of reactive oxygen species (ROS) and hydrogen peroxide in mitochondria, enhanced mitochondrial membrane potential (Δψm), upregulated B-cell leukemia/lymphoma-2 (Bcl-2) protein expression, and downregulated Bcl-2-associated X (Bax) protein and the ratio of cleaved-caspase-3/caspase-3, ultimately reducing cardiomyocyte apoptosis and preserving cardiac function by alleviating mitochondrial dysfunction [37].

Ginsenosides exhibit anti-inflammatory, antioxidant, and antiapoptotic effects [21]. Ginsenoside Rb1, a major component of Ginsenosides, can suppress the expression of inflammatory cytokines and modulate the Bax/Bcl-2 ratio, thereby inhibiting apoptosis in cardiomyocytes via blocking the Toll-like receptor 4 (TLR4)/NF-κB/pyrin domain-containing protein 3 (NLRP3) pathway [22]. This compound was shown to reduce mitochondrial ROS production, decrease lactate accumulation, and restore ATP levels in ischemia/reperfusion (I/R)-affected cardiomyocytes in a mouse model. Additionally, ginsenoside Rb1 played a cardioprotective role via inhibiting nicotinamide adenine dinucleotide dehydrogenase activity in mitochondrial complex I, attenuating cardiac fibrosis, reducing cardiomyocyte apoptosis, and alleviating oxidative damage [38]. It also significantly lowered the serum levels of TNF-α and IL-6 in mice with cancer cachexia, thus reducing inflammation and alleviating cachexia [23].

Notoginsenoside R1, a key active ingredient of Panax notoginseng, is known for its cardioprotective properties through anti-inflammatory, antioxidant, and pro-survival actions [24]. It has been effective in preventing changes in LVEF, LV fractional shortening, LVDd, and LVDs caused by LPS-induced inflammation, reducing leukocytic infiltration, inhibiting the expression of TNF-α, IL-1β, and IL-6, and attenuating the inflammation-induced reduction of endothelial nitric oxide synthase and inducible nitric oxide synthase (iNOS) enzymes via inhibiting the NF-κB signaling pathway [25, 26]. Moreover, Notoginsenoside R1 significantly improved cardiac function in heart failure models and reduced cardiac lipidosis by upregulating phosphorylated AMP-activated protein kinase and carnitine palmitoyltransferase IA [39]. It also protected against cardiac ischemia/reperfusion injuries by downregulating endoplasmic reticulum stress and oxidative stress [58], promoted cardiac cell survival by disinhibiting the PI3K/Akt pathway, as well as inhibiting the phosphatase and tensin homolog deleted on chromosome ten (PTEN), a target of miR-21, and reduced the expression of Bax and caspase-3 [47]. Additionally, Notoginsenoside R1 reduced cardiac fibrosis by inhibiting mRNA expression of α-SMA, collagen I, and fibronectin and alleviated myocardial injury by suppressing the activity of transforming growth factor β-activated protein kinase 1 (TAK1)/c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase 14 (p38/MAPK) TAK1/JNK/p38 signaling pathway [59].

Salidroside, the primary active ingredient of Rhodiola rosea, exhibits antiapoptotic, anti-inflammatory, and antioxidant properties. It promotes cardioprotection by enhancing angiogenesis and providing protection against ischemia [60]. Salidroside inhibits cardiac apoptosis by upregulating Bcl-2 protein expression and decreasing the expression of Bax protein [48]. Additionally, it blocks the JNK activation pathway, thereby preserving mitochondria from damage by preventing the release of cytochrome C, contributing further to cardioprotection [49]. Salidroside has also been shown to significantly reduce ST segment elevation and normalize serum levels of creatine kinase-MB, LDH, TNF-α, and IL-6; increase superoxide dismutase (SOD) activity; and decrease malondialdehyde (MDA) content in heart by inhibiting the Nox/NF-κB/AP1 pathway [27]. Similar anti-inflammatory and antioxidant effects were observed in I/R-induced AC16 cell damage, which Salidroside ameliorated by inhibiting the circ_0097682/miR-671-5p/USP46 pathway [28].

Clinical and pharmacological research has demonstrated that tanshinone IIA offers protection against ischemia and hypoxia and improves cardiovascular endothelial function. It is used clinically as an adjunctive treatment for coronary heart disease to improve myocardial ischemia [61]. Tanshinone IIA also provides cardioprotection through antiapoptotic, anti-inflammatory, and pro-survival mechanisms. It modulates the expression levels of Bax and Bcl-2 proteins, reduces the concentration of MDA in the heart, and mitigates myocardial I/R injury by decreasing the expression and release of TNF-α and IL-6 [29]. Additionally, Tanshinone IIA has been shown to significantly improve cardiac function in rat models of heart failure by regulating the AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) pathway to promote autophagy [40]. It inhibits the activity of caspase-3 and -8 and suppresses the activation of NF-κB/TNF-α pathway. Moreover, Tanshinone IIA deactivates JNK activity by activating the PI3K/Akt pathway, thus preventing cardiomyocyte apoptosis and enhancing cardioprotection [30].

Astragalus polysaccharides are known for their antiapoptotic, anti-inflammatory, and antioxidatant effects. This compound modulates cardiac contraction, potentially enhancing or inhibiting it based on dosage, and has been used in the clinical treatment of myocarditis. Studies have shown that Astragalus polysaccharides decrease LVEDD and left ventricular end-systolic diameter and reduce the rate of cardiomyocytes apoptosis. It influences myocardial contraction and cell apoptosis by regulating mitochondrial energy metabolism [50]. Astragalus polysaccharides decreases the levels of CK-MB, aspartate transaminases (AST), and LDH, reduces inflammation by suppressing TNF-α, IL-1β, IL-6, and monocyte chemotactic protein 1 expression, and enhances cardiac function by inhibiting the TLR4/NF-κB pathway [31]. It also lowers the level of ROS in cardiomyocytes, increases the activity of SOD and glutathione peroxidase, reduces MDA and NO levels, and activates the neuregulin-1/erythroblastic oncogene B and PI3K/Akt pathways, thereby inhibiting myocardial apoptosis [41].

Salvianolate, extracted from Salvia, is a key active ingredient in the clinical treatment of heart failure [62]. Clinical and pharmacological studies have shown that Salvianolate improves circulation and offers protection against inflammation, apoptosis, and oxidation [62]. Pharmacologically, it has been shown to increase LVEF and levels of heart-type fatty acid-binding protein. Salvianolate reduces inflammation by lowering the levels of IL-6 and TNF-α and decreasing the mRNA expression and transcription of TLR4 and the phosphorylation level of signal transducer and activator of transcription 3 [32]. It also induces antiapoptosis effects in cardiomyocytes via upregulating Bcl-2 expression and downregulating the expression of miR-122-5p, Bax, and caspases-3 [51]. Salvianolate also had the effects of reducing the level of myocardial necrosis markers (TnT, CK-MB, LDH), alleviating mitochondrial dysfunction of cardiomyocytes and inhibiting oxidative damage of mitochondrial DNA [42]. It was demonstrated that Salvianolate increased the level of extracellular signal-regulated protein kinase 1/2 phosphorylation to reduce myocardial damage and achieve cardioprotection [52].

Salvianolic acid A is recognized for its anti-inflammatory, antiapoptosis, antioxidative, and antithrombotic properties [63]. Studies indicate that salvianolic acid A reduces the levels of myocardial injury markers (LDH and AST) and diminishes inflammation by inhibiting the expression of TNF-α, IL-6, cyclooxygenase-2, and iNOS. It plays an important role in preventing cardiac fibrosis by reducing collagen content through inhibition of the Toll-like receptor/myeloid differentiation factor 88/TNF receptor-associated factor/NF-κB (TLR/Myd88/TRAF/NF-κB) signaling pathway [33]. Salvianolic acid A also reduces the levels of AST, LDH, and CK-MB, increases the ratio of Bcl-2/Bax, and inhibits the activation of Caspases 3 and 9. Additionally, it regulates the mitochondrial respiration function of cardiomyocytes by activating the inositol-requiring enzyme 1-Crystallin Alpha B (IRE1-CRYAB) signaling pathway [53]. Salvianolic acid A increases myocardial ATP levels, reduces ROS production, prevents the loss of Δψm by inhibiting the activation of mPTP, and activates the Akt/glycogen synthase kinase-3β pathway in hypoxia/reoxygenation cardiomyocytes [43].

Salvianolic acid B has demonstrated antiapoptotic, anti-inflammatory, antioxidative, and other beneficial effects. It significantly increases stroke volume, LVEF, fractional shortening, and cardiac output by enhancing the Bcl-2/Bax ratio, activating the PI3K/Akt pathway, and inhibiting the expression of high mobility group protein 1 (HMGB1). It also suppresses the levels of L-LDH, CK-MB, TNF-α, and IL-18 in a dose-dependent manner in I/R injury animal models [34]. Salvianolic acid B enhances the activity of antioxidant enzymes, SOD, and CAT to scavenge intracellular ROS, thereby reducing oxidative stress and apoptosis in the heart [44]. Moreover, its cardioprotective effects are linked to the inhibition of mammalian target of rapamycin complex 1-induced glycolysis. Salvianolic acid B decreases the level of M1 macrophages, increases the level of anti-inflammatory M2 macrophages, and reduces collagen deposition to improve cardiac function [64]. It inhibits the expression of collagen types I (Col I) and III (Col III) and significantly reduces the expression of insulin-like growth factor binding protein 3 (IGFBP3), Akt, and extracellular signal-regulated protein kinase phosphorylation, thus alleviating cardiac dysfunction and reducing cardiac fibrosis [54].

Ginkgolide A has been shown to exhibit anti-inflammatory and antioxidant effects. It can downregulate the expression of Col I, Col III, and fibronectin and reduce the levels of atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain, thereby alleviating cardiac fibrosis [65]. The anti-inflammatory and pro-survival activities of Ginkgolide A are associated to the inhibition of TLR4/NF-κB signaling and the activation of PI3K/Akt pathway. It also inhibits NF-κB signal activation, reduces the release of IL-6 and IL-8, and decreases the expression of TLR4 mRNA [35]. Additionally, Ginkgolide A plays a crucial role in enhancing cardiac function by inhibiting the production of ROS, reducing LDH production, and increasing the activity of SOD [45].

Ginkgolide B has demonstrated anti-inflammatory, antioxidant, and antiatherosclerotic effects. It reduces the levels of TNF-α, IL-1β, and IL-6 as well as the expression of intercellular adhesion molecules-1, vascular cell adhesion molecule-1, and iNOS. Furthermore, Ginkgolide B decreases the translocation of NF-κB p65, the phosphorylation of the inhibitory subunit of NF-κB-α (IκB-α), and the activity of inhibitor of kappa light polypeptide gene enhancer in B cells, kinase-β (IKK-β), while increasing the expression of the A20 gene [36]. It also reduces LDH activity and the degradation of myolipids, contributing to improved cardiac function [46]. Ginkgolide B additionally regulates the apoptotic balance by upregulating the ratio of Bcl-2/Bax, downregulating the expression of cleaved caspase-3, and activating the PI3K/Akt/mTOR signaling pathway in cardiomyocytes to achieve cardioprotection [55].

To enhance the targeting of drug delivery vectors, numerous studies have focused on developing nano-delivery systems, including lipid nanoparticles and inorganic nanoparticles [66]. Nanomaterials, small in size but large in specific surface area, can accumulate in significant numbers at the lesion site through enhanced penetration and retention, thereby achieving precise treatment and reducing the possibility of adverse reactions and disease complications.

Liposomal nano-drug delivery is the most advanced and widely used system, noted for its excellent biocompatibility. These systems often incorporate modifications that target highly expressed receptors on the surfaces of specific cells. By binding specifically to these receptors, liposomes can deliver drugs or mRNA directly into the cells. Liposomal microcapsules, commonly used as drug carriers, enhance the solubility and stability of drug active ingredients, prolong the drug action time, and improve drug specificity and targeting of disease sites [67]. Several studies have demonstrated the effectiveness of targeted nanoliposomes in delivering TCM monomers for CICC. Administered intravenously, these nanoliposomes circulate to the infracted heart, where they target macrophages and blood vessels [68]. Additionally, angiotensin II type 1 receptor-targeted nano-liposomes have been designed specifically to bind to cardiomyocytes [69]. Liposome-loaded ATP and CoQ10-L have shown high intracellular accumulation in experimental models of ischemic heart disease [70]. The use of a CD47 mimicry peptide on the surface of nanoliposomes has improved the residence time of liposomal doxorubicin in the circulation and reduced drug accumulation in nontarget tissues, potentially minimizing its toxicity [71]. Nano-liposomal encapsulation of [Pyr1]-Apelin-13 polypeptide has attenuated pressure overload-induced cardiac dysfunction [72]. Furthermore, the administration of liposomal FK506 has markedly suppressed the expression of interferon-γ and TNF-α, reducing inflammation and fibrosis in the myocardium, which outperformed free FK506 in ameliorating cardiac dysfunction and emerged as a promising delivery system for cardioprotective agents [73].

Inorganic delivery vehicles include gold nanoparticles, silica nanoparticles, and iron oxide nanoparticles. These can be tailored to specific sizes, structures, and geometries, making them suitable for delivering TCM monomers for CICC. Studies have developed a mesoporous silica nanoparticle-conjugated with a CD11b antibody loaded with Notoginsenoside R1 [74]. This design allows for precise, noninvasive targeted delivery of NGR1 to the heart, improving cardiac function and angiogenesis, reducing apoptosis, and regulating macrophage phenotype as well as inflammatory cytokines and chemokines. A calcium carbonate nano-delivery system was devised to load colchicine, addressing potential adverse reactions from high-dose usage. This system transported colchicine directly to the heart at myocardial infarction (MI) sites, enhancing the drug’s efficacy and reducing adverse reactions with a good safety profile and the ability to inhibit TNF-α and IL-1β and improve myocardial fibrosis [75]. Furthermore, Fe₃O₄-centric nanoparticles decorated with a polyethylene glycol silica shell were engineered to bind to two types of antibodies via hydrazone bonds. These antibodies target CD63 antigens on the surface of extracellular vesicles or myosin light-chain surface markers on injured cardiomyocytes. When exposed to a local magnetic field, these nanoparticles accumulated and released their cargo at the site of injury, resulting in a reduction in MI area and an improvement in LVEF and angiogenesis [76].

Exosomes are nanoscale membranous vesicles released into the extracellular matrix following the fusion of intracellular multivesicular bodies with the cell membrane. Naturally present in various body fluids, such as blood, saliva, urine, and milk, exosomes have been clinically validated as effective vehicles in cancer therapy [77]. Given these properties, exosomes are being explored as novel vectors for the treatment of various CVDs, including CICC. Compared to liposomes and polymer nanoparticles, exosomes offer superior biocompatibility and safety. Their ability to traverse the blood-brain barrier and their asymmetrical lipid bilayer structure facilitate efficient fusion with target cells [78, 79]. Exosomes can be loaded with diverse therapeutic agents including small molecules, macromolecules, proteins, nucleic acids, and natural products. They serve as drug delivery vehicles, homing in on specific diseases or delivery sites within the body. For instance, endothelial progenitor cell-derived exosomes have been shown to enhance angiogenesis, while stem cell-derived exosomes have targeted the heart to provide cardioprotection. Research utilizing C-kit⁺ progenitor cell spheroid-derived exosomes showed that exosome-mediated miRNA delivery effectively promotes angiogenesis and reduces fibrosis in vitro [80]. In addition, research has advanced in developing biomimetic nanovesicles to emulate the function of natural exosomes. For example, liposomes loaded with erythropoietin and CD15s delivered to a rabbit model of MI reduced infarct size, improved left ventricular function, and induced cardiac remodeling through proangiogenic and antifibrotic signaling [81]. Another study used synthetic nanoparticles encapsulated within membranes of cardiosphere-derived stem cells as therapeutic agents for MI in a mouse model, preserving cardiac survival and reducing T-cell infiltration. This highlights the potential of synthetic nanovesicle exosomes as effective carriers [82]. Milk-derived exosomes are emerging as promising candidates for the development of new treatments for CVDs. Studies have shown that milk exosomes can alleviate the deposition of the extracellular matrix in rats with cardiac fibrosis, significantly enhancing cardiac function by introducing proangiogenic factors [83]. The innovation in biomimetic nanomaterials also includes the construction of suitable membranes and the modification of extracellular vesicles based on biomimetic cell membranes, further broadening the therapeutic potential of exosome-based delivery systems.

In conclusion, TCM monomers have shown great potential and offer diverse treatment options in the field of CICC therapy. They exert their effects through mechanisms of anti-inflammation, antioxidation, and pro-survival by regulating ILs/TNF-α, ROS, and the PI3K/Akt pathway (Fig. 1). Cancer cachexia is postulated to result in cardiac atrophy/heart failure, leading to loss of cardiac function. Heart failure itself can be precipitated by cancer cachexia, and when developed, heart failure can augment the severity of existing cancer cachexia [84]. As heart failure is both an inflammatory and oxidative disease, cardiac cachexia should be diagnosed when body weight loss exceeds 6%, irrespective of other criteria and in the absence of other severe diseases [85‒87]. Hence, we believe that TCM monomers with their anti-inflammatory, antioxidative effects, and ability to upregulate protein synthesis hold promising potential for treating cancer-induced cardiac cachexia. However, further experiments are necessary to determine the precise efficacy of TCM monomers for this application. Before these TCM monomers can be incorporated into clinical practice, extensive preclinical studies and clinical trials are essential to confirm their safety and efficacy, so thus providing safer and more effective treatment options for patients with CICC. Future research should focus on establishing the optimal dosage, treatment duration, and potential drug interactions for these monomers to ensure that patients receive the maximum therapeutic benefit.

The authors have no conflicts of interest to declare.

This work was supported by the National Natural Sciences Foundation of China (82270295), the Special Clinical Research Project of Shanghai Municipal Health Commission (20204Y0378), the construction project of high-level local universities, the Shanghai University of Medicine and Health Sciences (E1-2601-23-201006), and the Construction project of Shanghai Key Laboratory of Molecular Imaging (18DZ2260400).

ZhiZheng Li, Xinyi Peng, and Xinyi Zhu drafted the manuscript. Lan Wu designed the figure and the table. ZhiZheng Li made the figure and the table. Lan Wu and Michail Spanos edited and revised the text. All authors approved the final version for submission.

Zhizheng Li, Xinyi Peng, and Xinyi Zhu contributed equally to this work.