Mitochondrial dysfunction with decreased ATP production and increased release of reactive oxygen species (ROS) is a hallmark of the failing heart. Although SGLT2 inhibitors have been shown to improve myocardial metabolism in the failing heart, independent of diabetes, the effect on mitochondria is not clear.

Our goal was to test the effect of the SGLT2 inhibitor ertugliflozin on mitochondrial gene expression and function in myocardium and isolated mitochondria from non-diabetic mice with dilated cardiomyopathy due to cardiac-specific over-expression of Gαq.

Gαq and wild type (WT) littermates 4 weeks of age were treated for 16 weeks with or without the SGLT2 inhibitor ertugliflozin (ERTU) formulated in the chow (0.5 mg/g chow).

From weeks 4 to 20, Gαq mice developed progressive cardiac hypertrophy, dilation, contractile dysfunction, myocyte apoptosis and interstitial fibrosis - all of which were prevented by ERTU treatment. Isolated cardiac mitochondria from Gαq mice had decreased maximal ATP production and increased ROS release - both of which were normalized by ERTU. In isolated beating hearts from Gαq mice, contractile reserve and high energy phosphates measured simultaneously by 31P NMR spectroscopy were decreased - and both were improved by ERTU. In Gαq mice, marked suppression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism was reversed by ERTU.

The SGLT2 inhibitor ERTU corrected the expression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism, and was associated with increased production of ATP, decreased release of mitochondrial ROS, and amelioration of the consequences of mitochondrial dysfunction on myocardial structure and function.

Increased activity of acid sphingomyelinase (ASMase) has been linked to diabetes and organ fibrosis. Nevertheless, the precise influence of ASMase on diabetic myocardial fibrosis and the corresponding molecular mechanisms remain elusive. In this study, we aim to elucidate whether ASMase contributes to diabetic myocardial fibrosis through the phosphorylation mediated by MAPK, thereby culminating in the development of diabetic cardiomyopathy (DCM). In vitro experiments utilized cardiac fibroblasts (CFs) isolated from wild-type mice (WT). For in vivo studies, ASMase knockout mice were generated through TALEN gene editing technology. Additionally, a diabetes mellitus model was established by intraperitoneal injection of Streptozotocin (STZ), involving both ASMase knockdown mice (ASMase+/--STZ) and WT mice. CFs were subjected to incubation with amitriptyline (AMP) (2.5 μM), advanced glycation end products (AGEs), and small interfering RNA (siRNA) over a duration of 24 h. Experimental assessments encompassed EdU incorporation, transwell assays, and fluorescence staining, aimed at elucidating the functional characteristics of cardiac fibroblasts. The quantification of collagen I, phosphorylated MAPK levels within both cellular and murine cardiac contexts was accomplished through Western blot analysis. In the ASMase±-STZ group, mice exhibited attenuated myocardial fibrosis and ameliorated cardiac diastolic function in comparison to the WT-STZ group. Furthermore, treatment of CFs with AMP and siRNA demonstrated a suppressive effect on the proliferation and fibrotic expression induced by AGEs in CFs. Our investigation unveiled that ASMase modulates myocardial fibrosis through the TGF-β-Smad3 and MAPK pathways, elucidating the intricate molecular mechanisms underlying the observed effects. Our findings indicate that ASMase plays a vital role in myocardial fibrosis in DCM, providing a foundation for developing new therapeutic strategies for the prevention and control of DCM.

Hyperuricemia and diabetes mellitus (DM) are prevalent metabolic disorders with high comorbidity, imposing a substantial global public health burden. Their coexistence is not merely additive but synergistic, exacerbating metabolic dysregulation through mechanisms such as insulin resistance and β-cell apoptosis, ultimately establishing a vicious cycle. Both disorders induce acute and chronic damage to vital organs, particularly the cardiovascular, renal systems. Hyperuricemia aggravates diabetic complications, notably diabetic cardiomyopathy, nephropathy and retinopathy via oxidative stress, inflammation, and metabolic dysregulation.Current urate-lowering therapies (ULTs), such as xanthine oxidase inhibitors and urate transporter 1 (URAT1, also known as SLC22A12) antagonists, demonstrate potential benefits in ameliorating diabetic complications but face challenges including safety concerns and dose adjustments. Similarly, several glucose-lowering drugs also exhibit the benefits of improving hyperuricemia. This review summarizes the metabolic crosstalk and therapeutic interplay between hyperuricemia and DM, examines the pathogenic role of uric acid in diabetic complications, and discusses the benefits and challenges of existing ULTs and glucose-lowering drugs in disrupting this cycle of metabolic dysregulation and concurrent organ damage. We hope our findings deepen the comprehension of the intricate metabolic crosstalk between glucose and urate homeostasis, providing novel therapeutic insights for patients with comorbid DM and hyperuricemia.

Doxorubicin (DOX), a classical chemotherapeutic agent, remains indispensable in cancer treatment but is limited by dose-dependent cardiotoxicity. Investigating strategies to mitigate DOX-induced cardiac damage is critical. Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, exhibits anti-inflammatory and antioxidant effects in cardiovascular disease. This study investigated empagliflozin's protective effects against DOX-induced cardiotoxicity and underlying mechanisms.

DOX-induced cardiotoxicity models were established in male C57BL/6 J mice, with cardiac-specific RIPK1 overexpression achieved via adeno-associated virus (AAV9) technology. Cardiac function was assessed using echocardiography, and heart tissue was analyzed for injury, inflammation, oxidative stress, endoplasmic reticulum (ER) stress, and autophagy through various biochemical and molecular assays.

Empagliflozin alleviated DOX-induced cardiac dysfunction, reduced fibrosis, and suppressed systemic inflammation and oxidative stress in mice. Mechanistic studies revealed that empagliflozin mitigated DOX-induced cardiotoxicity by inhibiting ER stress and autophagy, as evidenced by the downregulation of BIP, p-IRE1, and ATF6 expression, alongside elevated p62 and reduced LC3BII/LC3BI levels. RIPK1 was identified as a crucial mediator of empagliflozin's cardioprotective effects, with similar protection observed using the RIPK1 inhibitor Nec-1. RIPK1 knockdown in cardiomyocytes mimicked empagliflozin's antioxidant effects, while its protective effects were abolished in RIPK1-deficient cells. Importantly, RIPK1 overexpression reduced empagliflozin's benefits in DOX-treated mice. In addition, empagliflozin enhanced DOX-induced cytotoxicity in 4 T1 breast cancer cells.

Empagliflozin protects against DOX-induced cardiotoxicity by attenuating inflammation, oxidative stress, ER stress and autophagy, primarily through RIPK1 inhibition, providing insights into its cardioprotective mechanisms. Additionally, empagliflozin enhances DOX-induced cytotoxicity in vitro, providing support for its combination with DOX in cancer therapy.

In adults, expressed in renal cancer (ERC)/mesothelin is exclusively expressed in the mesothelial cells lining the pleural, pericardial, and peritoneal cavities, yet its function under physiological conditions is unknown. To explore this, we studied ERC expression in wild-type (WT) mice at different developmental stages by immunohistochemistry and analyzed the ultrastructure of the mesothelium in WT and Erc-knockout (KO) mice via electron microscopy. Additionally, cardiopulmonary function in adult WT and Erc-KO mice was assessed using echocardiography and the forced oscillation technique (FOT). During embryonic development in WT mice, ERC expression was detected in the epicardium as early as embryonic day (E)12.5 but was absent in the pleura until E18.5. The timing of expression appeared to coincide with the active maturation of these organs, which implied a potential role in cardiopulmonary development. Electron microscopy revealed that microvilli on the mesothelium of Erc-KO mice were immature compared to those of WT mice. Based on these findings, we hypothesized that ERC might contribute to cardiopulmonary function; however, echocardiography and FOT did not reveal any functional differences between WT and Erc-KO mice. This suggests that ERC has limited functional relevance under physiological conditions.

High throughput immunoassay is increasingly crucial for both scientific and clinical applications. Here we propose a "Lab-in-a-Tip" (LIT) concept to fabricate a pipette tip containing a high-density protein array and other essential reagents. The protein array is made by self-assembling digitally encoded microparticles inside the modified tip. Mounted on a robotic workstation, it automates liquid-handling steps. Notably, compared with Luminex, the current gold standard in multiplex immunoassays, such a design enables LIT to demonstrate multiple advantages in terms of analytical sensitivity, speed, and throughput. It detects analyte concentrations as low as fg/ml, representing a sensitivity improvement of two orders of magnitude over Luminex. Incubation time is reduced to 15 minutes from Luminex's 210 minutes. Furthermore, LIT requires only 10 µl of sample, one-fifth of what Luminex needs. This makes LIT ideal for rapid diagnostics and studies with limited biological samples, greatly expanding its application scope.

The discovery of ferroptosis has brought a revolutionary breakthrough in heart failure treatment, and natural products, as a significant source of drug discovery, are gradually demonstrating their extraordinary potential in regulating ferroptosis and alleviating heart failure symptoms. In addition to chemically synthesized small molecule compounds, natural products have attracted attention as an important source for discovering compounds that target ferroptosis in treating heart failure.

Systematically summarize and analyze the research progress on improving heart failure through natural products' modulation of the ferroptosis pathway.

By comprehensively searching authoritative databases like PubMed, Web of Science, and China National Knowledge Infrastructure with keywords such as "heart failure", "cardiovascular disease", "heart disease", "ferroptosis", "natural products", "active compounds", "traditional Chinese medicine formulas", "traditional Chinese medicine", and "acupuncture", we aim to systematically review the mechanism of ferroptosis and its link with heart failure. We also want to explore natural small-molecule compounds, traditional Chinese medicine formulas, and acupuncture therapies that can inhibit ferroptosis to improve heart failure.

In this review, we not only trace the evolution of the concept of ferroptosis and clearly distinguish it from other forms of cell death but also establish a comprehensive theoretical framework encompassing core mechanisms such as iron overload and system xc-/GSH/GPX4 imbalance, along with multiple auxiliary pathways. On this basis, we innovatively link ferroptosis with various types of heart failure, covering classic heart failure types and extending our research to pre-heart failure conditions such as arrhythmia and aortic aneurysm, providing new insights for early intervention in heart failure. Importantly, this article systematically integrates multiple strategies of natural products for interfering with ferroptosis, ranging from monomeric compounds and bioactive components to crude extracts and further to traditional Chinese medicine formulae. In addition, non-pharmacological means such as acupuncture are also included.

This study fills the gap in the systematic description of the relationship between ferroptosis and heart failure and the therapeutic strategies of natural products, aiming to provide patients with more diverse treatment options and promote the development of the heart failure treatment field.

Ferroptosis, a form of iron-dependent regulated cell death, has emerged as a critical mechanism in the pathogenesis of organ fibrosis. This review aims to provide an overview of the molecular mechanisms underlying ferroptosis and its contribution to fibrosis in various organs, including the liver, lung, heart, and kidneys. We explore how dysregulated iron metabolism, lipid peroxidation, and oxidative stress contribute to ferroptosis and subsequent tissue damage, promoting the progression of fibrosis. In addition, we highlight the complex interplay between ferroptosis and other cellular processes such as apoptosis, necrosis, and inflammation in the fibrotic microenvironment. Furthermore, this review discusses current therapeutic strategies targeting ferroptosis, including iron chelation, antioxidants, and modulators of lipid peroxidation. We also examine ongoing clinical and preclinical studies aimed at translating these findings into viable treatments for fibrotic diseases. Understanding the role of ferroptosis in organ fibrosis offers novel therapeutic opportunities, with the potential to mitigate disease progression and improve patient outcomes.

Diabetes mellitus (DM) and neuroendocrine tumors (NET) can exert unfavorable effects on each other prognosis. In this narrative review, we evaluated the effects of NET therapies on glycemic control and DM management and the effects of anti-diabetic therapies on NET outcome and management. For this purpose, we searched the PubMed, Science Direct, and Google Scholar databases for studies reporting the effects of NET therapy on DM as well as the effect of DM therapy on NET. The majority of NET treatments appear to impair glycaemic control, both inducing hypoglycemic or, more commonly, hyperglycemia and even new-onset DM. However, glucose metabolism imbalance can be effectively managed by modulating anti-diabetic therapy and adopting an appropriate nutritional approach. On the other hand, the effects of anti-diabetic treatment, like insulin, sulfonylureas, thiazolidinediones, ipeptidyl-peptidase-4 inhibitors, Glucagon-like peptide-1 receptor agonists, and Sodium-glucose cotransporter-2 inhibitors on NET are unclear. Recently, metformin has been investigated in patients with gastroenteropancreatic NET resulting in improved progression free survival suggesting a potential antineoplastic role. Finally, the management of DM in patients with NET is of great clinical relevance to correctly perform radiological procedures and even more functional imaging procedures, as well as to optimize the therapy and avoid treatment withdrawal or discontinuation. In conclusion, understanding the mechanisms underlying therapy-induced DM and implementing appropriate monitoring and management strategies of DM are essential for optimizing NET patient outcome and quality of life.

Cardiovascular-kidney-metabolic (CKM) syndrome represents a complex interplay between cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic disorders, significantly impacting cancer patients. The presence of CKM syndrome in cancer patients not only worsens their prognosis but also increases the risk of major adverse cardiovascular events (MACE), reduces quality of life (QoL), and affects overall survival (OS). Furthermore, several anticancer therapies, including anthracyclines, tyrosine kinase inhibitors, immune checkpoint inhibitors, and hormonal treatments, can exacerbate CKM syndrome by inducing cardiotoxicity, nephrotoxicity, and metabolic dysregulation. This review explores the pathophysiology of CKM syndrome in cancer patients and highlights emerging therapeutic strategies to mitigate its impact. We discuss the role of novel pharmacological interventions, including sodium-glucose cotransporter-2 inhibitors (SGLT2i), proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), and soluble guanylate cyclase (sGC) activators, as well as dietary and lifestyle interventions. Optimizing the management of CKM syndrome in cancer patients is crucial to improving OS, enhancing QoL, and reducing MACE. By integrating cardiometabolic therapies into oncologic care, we can create a more comprehensive treatment approach that reduces the burden of cardiovascular and renal complications in this vulnerable population. Further research is needed to establish personalized strategies for CKM syndrome prevention and treatment in cancer patients.

Doxorubicin (DOX), a widely utilized anthracycline chemotherapy agent, is known for its potent anticancer efficacy across various malignancies. However, its clinical use is considerably restricted due to the risk of dose-dependent cardiotoxicity, which can lead to long-term heart dysfunction. The underlying mechanism of DOX-induced cardiotoxicity has been associated with the formation of reactive oxygen species (ROS) and disrupting cellular signaling pathways. This is particularly relevant to the activation of the NLRP3 inflammasome, which triggers inflammation and pyroptosis in cardiac cells. In recent years, there has been growing interest in natural compounds that exhibit potential cardioprotective effects against the adverse cardiac effects of DOX. The present study showed that specific natural compounds, such as honokiol, resveratrol, cynaroside, and curcumin, can confer significant protection against DOX-induced cardiotoxicity through the modulation of NLRP3 inflammasome signaling pathways. In summary, incorporating natural compounds into treatment plans could be a practical approach to improve the safety profile of DOX, thereby protecting cardiac health through the regulation of the NLRP3 pathway.

Late-onset cardiotoxicity induced by anthracyclines occurs years to decades after completion of anti-cancer therapy and is associated with increased morbi-mortality of cancer survivors. Chemotherapy at the time of treatment probably causes cardiac damages for which the juvenile heart compensate. Co-morbidities happening in the adulthood such as type 1 diabetes (DT1), affect the heart and thus can unmask chemotherapy induced cardiotoxicity. To prove our hypothesis, we induced hyperglycemia [Streptozotocin treatment (STZ), 50 mg/kg/day for 5 days] in 11 weeks old mice who previously received doxorubicin treatment (Dox, 3 mg/kg) when they were six-weeks old. Interestingly, streptozotocin-induced hyperglycemia in Dox-pretreated mice (Dox-STZ) induced a higher mortality (p < 0.05) and more severe cardiac dysfunction (p < 0.0001) when compared with mice receiving Dox or STZ alone. Apoptosis evaluated by caspase 3 protein expression and Bax/Bcl2 genes expression was higher in Dox-STZ mice compared to STZ or Dox alone. While Dox and STZ independently induced capillary rarefaction, cardiomyocytes atrophy was only induced by STZ. Furthermore, Sirius-red staining of cardiac sections showed higher fibrosis levels (p < 0.0001) in Dox-STZ compared to Dox or STZ alone. All together, these results demonstrate that STZ precipitates and unmask cardiac dysfunction in previously treated Dox animals.

Renal risk variants in the apolipoprotein L1 (APOL1) gene confer protection against trypanosomiasis, but these risk variants (G1 and G2 variants) also predispose to kidney disease among individuals, especially from Sub-SaharanAfrica. Currently, the mechanisms of how these renal risk variants induce kidney damage are not precisely defined, but lysosomal and mitochondrial dysfunction, altered ion channel activity, altered autophagy, and disordered immunity are suggested. Currently, there is no specific treatment for APOL1 kidney disease (APOL1-KD) although several potential disease-specific therapeutic agents are being evaluated in clinical trials. Non-specific interventions include proteinuria screening, salt restriction, and renin-angiotensin-aldosterone system inhibition but are not sufficient to prevent kidney disease progression in APOL1-KD. Given the lack of specific treatment options, more efforts are necessary to reduce kidney disease progression. Sodium glucose co-transport-2 (SGLT2) inhibitors (SGLT2i) are gaining attention for benefits in proteinuric kidney diseases and exert many beneficial effects which theoretically may be beneficial in the context of APOL1-KD. These beneficial effects include but are not limited to increased natriuresis, decreased proteinuria/albuminuria, and mitochondrial dysfunction. SGLT2i have antioxidant, anti-inflammatory and anti-fibrotic effects. In the current review, we highlight the potential reasons for exploring the use of SGLT2i in APOL1-KD. Future studies are warranted to explore if SGLT2i use can provide protection in APOL1-KD.

Novel therapeutic strategies are essential for enhancing efficacy and accelerating the treatment of diabetes mellitus. This investigation focused on incorporating empagliflozin into a composite of polylactic acid and polycaprolactone, resulting in the fabrication of drug-loaded fibrous patches (DFPs) for transdermal application, both by electrospinning (ES) and by pressurized gyration (PG). Scanning electron microscopy results revealed that DFPs generated through the PG method exhibited smaller diameters and a larger surface area than ES. Fourier-transform infrared spectroscopy and X-ray powder diffraction analyses confirmed the successful encapsulation of the drug in both DFPs. DFPs/PG exhibited a controlled release of 98.7 ± 1.3% of the total drug over 14 days, while DFPs/ES released 98.1 ± 2.1% in 12 days, according to in vitro drug release studies. This study underscores that the PG method can generate DFPs with extended controlled release. 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide test results validate the biocompatibility of DFPs, affirming their lack of adverse effects on human dermal fibroblast cell viability. Consequently, DFPs can be manufactured for transdermal administration using PG, exhibiting similar characteristics to ES but with the added advantage of mass production capability.

The first sodium-glucose cotransporter-2 inhibitor (SGLT2I), canagliflozin, was approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in 2013. Since then, other members of this drug class (such as dapagliflozin, empagliflozin, and ertugliflozin) have become widely used. Unlike classical antidiabetic agents, these drugs do not interfere with insulin secretion or action, but instead promote renal glucose excretion. Since their approval, many preclinical and clinical studies have been conducted to investigate the diverse effects of SGLT2Is. While originally introduced as antidiabetic agents, the SGLT2Is are now recognized as pillars in the treatment of heart failure and chronic kidney disease, in patients with or without diabetes. The beneficial cardiac effects of this class have been attributed to several mechanisms. Among these, SGLT2Is inhibit fibrosis, hypertrophy, apoptosis, inflammation, and oxidative stress. They regulate mitochondrial function and ion transport, and stimulate autophagy through several underlying mechanisms. This review details the potential effects of SGLT2Is on cardiac cells.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is), commonly known as flozins, have garnered attention not only for their glucose-lowering effects in type 2 diabetes mellitus (T2DM) but also for their cardioprotective properties. This review examines the mechanisms underlying the anti-fibrotic effects of SGLT2is, with a focus on key clinical trials and preclinical models. SGLT2is, mainly empagliflozin and dapagliflozin, have demonstrated significant reductions in heart failure-related hospitalizations, cardiovascular death, and fibrosis markers, independent of their glucose-lowering effects. The cardioprotective benefits appear to stem from direct actions on cardiac tissues, modulation of inflammatory responses, and improvements in metabolic parameters. In animal models of heart failure, SGLT2is were demonstrated to reduce cardiac fibrosis through mechanisms involving AMPK activation, reduced oxidative stress, and inhibition of pro-fibrotic pathways, not only through the inhibition of SGLT2 present on cardiac cells but also by targeting several other molecular targets. These findings confirm their efficacy in the treatment of heart failure and align with evidence from human trials, supporting the potential involvement of multiple pathways in mediating cardiac fibrosis. These results also provide a promising basis for clinical trials specifically targeting pathways shared with SGLT2is.

The inclusion of immunomodulatory strategies as supportive therapies in ischemic heart disease (IHD) has garnered significant support over recent years. Several such approaches appear to be unified through their ultimate target, the NLRP3 inflammasome. This review presents a brief update on immunomodulatory strategies in the continuum of conditions constituting ischemic heart disease and emphasising on the seemingly unifying mechanism of NLRP3 activation as well as modulation across these conditions.

The NLRP3 inflammasome is a multiprotein complex assembled upon inflammatory stimulation, causing the release of pro-inflammatory cytokines and initiating pyroptosis. The NLRP3 pathway is relevant in inflammatory signalling of cardiac immune cells as well as non-immune cells in the myocardium, including cardiomyocytes, fibroblasts and endothelial cells. In addition to a focus on clinical outcome and efficacy trials of targeting NLRP3-related pathways, the potential connection between immunomodulation in cardiology and the NLRP3 pathway is currently being explored in preclinical trials. Colchicine, cytokine-based approaches and SGLT2 inhibitors have emerged as promising agents. However, the conditions comprising IHD including atherosclerosis, coronary artery disease (CAD), myocardial infarction (MI) and ischemic cardiomyopathy/heart failure (iCMP/HF) are not equally amenable to immunomodulation with the respective drugs. Atherosclerosis, coronary artery disease and ischemic cardiomyopathy are affected by chronic inflammation, but the immunomodulatory approach to acute inflammation in the post-MI setting remains a pharmacological challenge, as detrimental and regenerative effects of myocardial inflammation are initiated in unison. The NLRP3 inflammasome lies at the center of cell mediated inflammation in IHD. Recent trial evidence has highlighted anti-inflammatory effects of colchicine, interleukin-based therapy as well as SGLT2i in IHD and that the respective drugs modulate the NLRP3 inflammasome.

Doxorubicin (DOX), an anthracycline antibiotic, has limited clinical use due to its pronounced cardiotoxicity. Irisin, a myokine known for its metabolic regulation, has shown therapeutic effects on cardiovascular disease. This study investigates the potential cardioprotective function of irisin in reducing the cardiac injury induced by DOX.

In vitro, H9c2 cells were pretreated with irisin (20 nM) for 24 hours before exposure to DOX (1 μM). In vivo, C57BL/6 mice were administered DOX (5 mg/kg/week, i.p.) for 4 weeks, reaching a cumulative dose of 20 mg/kg. Irisin (1 mg/kg/ 3 days, i.p.) was administered to the mice both 7 days prior to and during DOX injection.Cardiac function was evaluated by echocardiography, and cardiac histology was assessed using HE, WGA, and Masson staining. Myocardial injury markers were quantified using ELISA, and apoptosis was analyzed via TUNEL staining. Oxidative stress was determined by measuring antioxidase activity, MDA and GSH levels, and DHE staining, while mitochondrial superoxide production was assessed using MitoSOX Red. Mitochondrial morphology and function evaluated using transmission electron microscopy and Seahorse analysis, respectively Inflammatory cytokines were quantified in serum and cell supernatants. The role of the PERK-eIF2α-ATF4 pathway mediated by irisin was investigated by Western blot. Using adeno-associated virus serotype-9 carrying mouse FNDC5 shRNA (AAV9-shFNDC5) further validated the protective role of irisin in DOX-induced myocardial injury.

Irisin reduced DOX-induced cardiac dysfunction and fibrosis. Moreover, irisin mitigated oxidative stress and inflammation through inhibiting the PERK-eIF2α-ATF4 pathway activated by DOX, thus preserving mitochondrial function. While cardiac FNDC5 knockdown exacerbated DOX-induced heart injury and PERK-eIF2α-ATF4 activation, which was partially reversed by irisin.

Irisin mitigates oxidative stress and inflammation by modulating the PERK-eIF2α-ATF4 pathway, highlighting its potential as a prospective approach for combating DOX-induced cardiotoxicity.

More evidence-based strategies are needed for preventing and managing cancer treatment-related cardiovascular toxicity (CTR-CVT). Owing to the growing body of evidence supporting their cardioprotective role in several cardiac injury scenarios, sodium-glucose cotransporter 2 inhibitors (SGLT2i) may be beneficial for preventing and treating CTR-CVT. In October 2024, a search was conducted of the PubMed database to review full studies investigating the cardioprotective role of SGLT2i against CTR-CVT. We identified 44 full published/pre-print studies and 3 ongoing randomised controlled trial across eight types of cancer treatment (anthracyclines, platinum-containing therapy, immune checkpoint inhibitors, HER2-targeted therapies, kinase inhibitors, androgen deprivation therapies, multiple myeloma therapies and 5-fluorouracil). Most studies used animal models and focussed on primary prevention. 43 of the 44 studies found some cardioprotective effect of SGLT2i against CTR-CVT, which in some cases included preventing ejection fraction decline and aberrations in cardiac electrophysiological parameters. Some studies also observed beneficial effects on mortality. A central triad of anti-inflammatory, anti-oxidative and anti-apoptotic mechanisms likely underlie SGLT2i-mediated cardioprotection against CTR-CVT. Overall, this growing body of research suggests that SGLT2i may be a promising candidate for preventing CTR-CVT either as monotherapy or in combination with other cardioprotective drugs. However, the literature is limited in that no prospective randomised controlled trials investigating SGLT2i for the prevention and management of CTR-CVT exist and most existing human retrospective data is based on diabetic populations. Future work must focus on addressing these limitations of the current literature.

Maintaining iron homeostasis is necessary for kidney functioning. There is more and more research indicating that kidney disease is often caused by iron imbalance. Over the past decade, ferroptosis' role in mediating the development and progression of renal disorders, such as acute kidney injury (renal ischemia-reperfusion injury, drug-induced acute kidney injury, severe acute pancreatitis induced acute kidney injury and sepsis-associated acute kidney injury), chronic kidney disease (diabetic nephropathy, renal fibrosis, autosomal dominant polycystic kidney disease) and renal cell carcinoma, has come into focus. Thus, knowing kidney iron metabolism and ferroptosis regulation may enhance disease therapy. In this review, we discuss the metabolic and molecular mechanisms of iron signaling and ferroptosis in kidney disease. We also explore the possible targets of ferroptosis in the therapy of renal illness, as well as their existing limitations and future strategies.

The prevalence of obesity and associated metabolic disorders such as diabetes is rapidly increasing; therefore, concerns regarding their cardiovascular consequences, including cardiac arrhythmias, are rising. As obesity progresses, the excessively produced lipids accumulate in unconventional areas such as the epicardial adipose tissue (EAT) around the myocardium. Metabolic alterations in obesity contribute to the transformation of these ectopic fat deposits into arrhythmogenic substrates. However, despite advances in therapeutic approaches, particularly in lowering EAT volume and thickness through sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, obese and diabetic patients still suffer from fatal arrhythmias that may lead to sudden cardiac death. Therefore, an investigation into how unappreciated underlying pathways such as lipid mediators contribute to the transformation of adipose tissues into proinflammatory and arrhythmogenic substrates is of significance. Leukotriene B4 (LTB4) is an eicosanoid derived from arachidonic acid and acts as a lipid mediator. LTB4 has recently been identified to be associated with cardiac ion channel modulations and arrhythmogenic conditions in diabetes. LTB4 increases circulatory free fatty acids (FFAs) and has been associated with adipocyte hypertrophy. LTB4 also interferes with insulin signaling pathways, instigating insulin resistance (IR). In addition, LTB4, as a potent chemoattractant, contributes to the mobilization of circulatory immune cells such as monocytes and promotes inflammatory macrophage polarization and macrophage dysfunction. Thus, this review provides a comprehensive overview of LTB4's underlying pathways in obesity; illustrates how these pathways might lead to alterations in cardiac ion channels, currents, and cardiac arrhythmias; and shows how they might pose a therapeutic target for metabolic-associated arrhythmias.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted their use in two frequently intertwined conditions, heart failure and chronic kidney disease. Their unique mechanism of action makes SGLT2i an attractive option also to lower the rate of cardiac events and improve overall survival of oncological patients with preexisting cardiovascular risk and/or candidate to receive cardiotoxic therapies. This review will cover biological foundations and clinical evidence for SGLT2i modulating myocardial function and metabolism, with a focus on their possible use as cardioprotective agents in the cardio-oncology settings. Furthermore, we will explore recently emerged SGLT2i effects on hematopoiesis and immune system, carrying the potential of attenuating tumor growth and chemotherapy-induced cytopenias.

Doxorubicin (DOX) is an important drug used in the treatment of many malignancies. Unfortunately DOX causes various side effects, with cardiotoxicity being the most characteristic. Risk factors for DOX induced cardiotoxicity (DIC) include cumulative dose of DOX, preexisting cardiovascular diseases, dyslipidemia, diabetes, smoking, along with the use of other cardiotoxic agents. Development of DIC is associated with many pathological phenomena - increased oxidative stress, as well as upregulation of ferroptosis, apoptosis, necrosis, and autophagy. In DIC expression of many microRNAs is also deregulated. In order to avoid cardiotoxicity and still use DOX effectively DOX derivatives such as epirubicin were synthesized. Nowadays a new liposomal form of DOX (L-DOX) appeared as an alternative to conventional treatment with greatly reduced cardiotoxicity. L-DOX can be divided into two groups of substances - pegylated (PLD) with increased solubility and stability, and non-pegylated (NLPD). Many metaanalyses, clinical along with preclinical studies have shown L-DOX treatment is associated with a smaller decrease of left ventricular ejection fraction (LVEF) and other heart functions, but efficacy of this treatment is comparable to the use of convenctional DOX.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been reported as successful for preventing doxorubicin (DOX) -induced cardiotoxicity (DIC), but the underlying mechanisms are elusive. This study aimed to determine whether canagliflozin, an SGLT2i, protects against DIC by regulation of autophagic flux in cardiomyocytes through a mechanism independent of SGLT2. The differentially expressed autophagy-related genes (ARGs) in DIC were analyzed. Neonatal rat cardiomyocytes (NRCMs), H9C2 rat cardiomyocytes or C57BL/6 mice were treated with canagliflozin or vehicle. The effects on cellular apoptosis and autophagy were investigated using qRT-PCR, western blotting and immunofluorescence. Additionally, cardiac function, myocardial fibrosis, and apoptosis of cardiomyocytes were also assessed in mice. The potential molecular targets of canagliflozin were identified through molecular docking analysis. A total of 26 differentially expressed ARGs were identified. Canagliflozin significantly activated autophagic flux and inhibited apoptosis of cardiomyocytes in both DOX-treated H9C2 rat cardiomyocytes and NRCMs. In a murine model of DIC, canagliflozin improved cardiac dysfunction by suppressing cardiac remodeling, fibrosis, and apoptosis. Moreover, canagliflozin promoted autophagy by enhancing SIRT1 levels and inhibiting the PI3K/Akt/mTOR signaling pathway. Immunofluorescence assays revealed that canagliflozin promoted the translocation of LC3 from the nucleus to the cytoplasm. Molecular docking analysis confirmed that canagliflozin has high affinity for targets associated with DIC. These findings suggest that canagliflozin protects cardiomyocytes from DOX-induced cell death by activating SIRT1, inhibiting the PI3K/Akt/mTOR pathway, and enhancing autophagic flux.

Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a common, highly heterogeneous condition that affects about a quarter of the world's population, with no approved drug therapy. Current evidence from preclinical research and a number of small clinical trials indicates that SGLT2 inhibitors could also be effective for MAFLD. MAFLD is associated with a higher risk of chronic liver disease and multiple extrahepatic events, especially cardiovascular disease (CVD) and chronic kidney disease (CKD). MAFLD is considered a more appropriate terminology than NAFLD because it captures the complex bidirectional interplay between fatty liver and metabolic dysfunctions associated with disease progression, such as obesity and type 2 diabetes mellitus (T2DM). SGLT2 inhibitors are antidiabetic drugs that block glucose reabsorption in the kidney proximal tubule. In this article, we reviewed current clinical evidence supporting the potential use of SGLT2 inhibitors as a drug therapy for MAFLD and discussed the possible cellular and molecular mechanisms involved. We also reviewed the clinical benefits of SGLT2 inhibitors against MAFLD-related comorbidities, especially CVD, CKD and cardiovascular-kidney-metabolic syndrome (CKM). The broad beneficial effects of SGLT2 inhibitors support their use, likely in combination with other drugs, as a therapy for MAFLD.

Sodium glucose co-transporter 2 (SGLT2) inhibitors represent a novel class of hypoglycemic drugs that have emerged in recent years. These inhibitors function primarily by blocking the reabsorption of glucose in the kidneys, specifically targeting the SGLT2 proteins in the proximal convoluted tubules. This inhibition results in the reduction of blood glucose levels through increased glucose excretion in the urine. Recent studies have identified SGLT2 expression in various cancer types, suggesting that SGLT2 inhibition can potentially suppress tumor growth. This article provides a comprehensive review of the role of SGLT2 in tumorigenesis and tumor progression, and explores the underlying mechanisms and potential therapeutic applications of SGLT2 inhibitors as anticancer agents.

Studies have confirmed that elevated glucose levels could lead to renal fibrosis through the process of ferroptosis. Liraglutide, a human glucagon-like peptide-1 (GLP-1) analogue, is a potential treatment option for diabetes. This study aimed to examine the potential of liraglutide (LIRA) in inhibiting ferroptosis and reducing high glucose-induced renal fibrotic injury in mice, and whether the Fsp1-CoQ10-NAD(P)H signal pathway is a mechanism for this effect. In our study, we used db/db mice to simulate Type 2 diabetes mellitus (T2DM). The mice were intraperitoneally injected with LIRA (200 µg/kg/d) daily for 6 weeks. Renal function, pathologic changes, lipid peroxidation levels, iron levels, and ferroptosis were assessed. First, LIRA ameliorated renal dysfunction and fibrosis in db/db mice. Second, LIRA inhibited lipid peroxidation by up-regulating T-SOD, GSH-Px, and GSH activities as well as down-regulating the levels of 8-OHDG, MDA, LPO, 4-HNE, 12-Lox, and NOX4 in db/db mice. In addition, LIRA attenuated iron deposition by decreasing the expression of TfR1 and increasing the expression of FPN1. Meanwhile, LIRA reduced high levels of high glucose-induced cell viability decline and intracellular lipid peroxidation. Furthermore, LIRA inhibited ferroptosis by adjusting the Fsp1-CoQ10-NAD(P)H pathway in vivo and in vitro. These findings suggested that LIRA attenuated kidney fibrosis injury in db/db mice by inhibiting ferroptosis through the Fsp1-CoQ10-NAD(P)H pathway.

Sodium/glucose co-transporter 2 (SGLT2) inhibitors have transformed heart failure (HF) treatment, offering sympatholytic effects whose mechanisms are not fully understood. Our previous studies identified Cyclic GMP-AMP synthase (cGAS)-derived neuroinflammation in the Subfornical organ (SFO) as a promoter of sympathoexcitation, worsening myocardial remodeling in HF. This research explored the role of central SGLT2 in inducing endothelial cGAS-driven neuroinflammation in the SFO during HF and assessed the impact of SGLT2 inhibitors on this process.

Hypertensive HF was induced in mice via Angiotensin II infusion for four weeks. SGLT2 expression and localization in the SFO were determined through immunoblotting and double-immunofluorescence staining. AAV9-TIE-shRNA (SGLT2) facilitated targeted SGLT2 knockdown in SFO endothelial cells (ECs), with subsequent analyses via immunoblotting, staining, and co-immunoprecipitation to investigate interactions with cGAS, mitochondrial alterations, and pro-inflammatory pathway activation. Renal sympathetic nerve activity and heart rate variability were measured to assess sympathetic output, alongside evaluations of cardiac function in HF mice.

In HF model mice, SGLT2 levels are markedly raised in SFO ECs, disrupting mitochondrial function and elevating oxidative stress. SGLT2 knockdown preserved mitochondrial integrity and function, reduced inflammation, and highlighted the influence of SGLT2 on mitochondrial health. SGLT2's interaction with cGAS prevented its ubiquitination and degradation, amplifying neuroinflammation and HF progression. Conversely, Empagliflozin counteracted these effects, suggesting that targeting the SGLT2-cGAS interaction as a novel HF treatment avenue.

This study revealed that SGLT2 directly reduced cGAS degradation in brain ECs, enhancing neuroinflammation in the SFO, and promoting sympathoexcitation and myocardial remodeling. The significance of the central SGLT2-cGAS interaction in cardiovascular disease mechanisms is emphasized.

The first part of this review highlighted the evolving landscape of atherosclerosis, noting emerging cardiometabolic risk factors, the growing impact of exposomes, and social determinants of health. The prominent role of atherosclerosis in the bidirectional relationship between cardiovascular disease and cancer was also discussed. In this second part, we examine the complex interplay between multimorbid cardio-oncologic patients, cardiometabolic risk factors, and the harmful environments that lend a "syndemic" nature to these chronic diseases. We summarize management strategies targeting disordered cardiometabolic factors to mitigate cardiovascular disease and explore molecular mechanisms enabling more tailored therapies. Importantly, we emphasize the early interception of atherosclerosis through multifactorial interventions that detect subclinical signs (via biomarkers and imaging) to treat modifiable risk factors and prevent clinical events. A concerted preventive effort-referred to by some as a "preventome"-is essential to reduce the burden of atherosclerosis-driven chronic diseases, shifting from mere chronic disease management to the proactive promotion of "chronic health".

During the last decades, progress in the treatment of oncological diseases has led to an increase in the survival of cancer patients: cancer survivors (CS). Thus, the incidence of CS has increased enormously, in both adult CS and childhood and adolescent CS. Unfortunately, CS treated with anthracyclines, chest radiotherapy (RT) and other potentially cardiotoxic drugs have a higher risk of cardiovascular (CV) toxicity: heart failure with reduced ejection fraction (HFrEF), valve diseases, coronary artery diseases, vascular diseases and pericardial diseases. In fact, chest irradiation can cause coronary artery diseases that can be latent until at least 10 years after exposure; also, valvular heart diseases can appear after >20 years following irradiation; heart failure may appear later, several years after anticancer drugs or RT. Therefore, it is very important to stratify the CV risk of cancer patients at the end of cardiotoxic drugs, to plan the most appropriate long-term surveillance program, in accordance with 2022 ESC Guidelines on Cardio-Oncology, to prevent late cardiovascular complications. Monitoring of cancer patients must not stop during anticancer treatment but it must continue afterwards, depending on the patient's CV risk. CV toxicity risk should be reassessed 5 years after therapy to organize long-term follow-up. Considering late cardiotoxicity in CS, our review aims to evaluate the incidence of cardiovascular diseases in CS, their mechanisms, surveillance protocols, preventive strategies, diagnosis and treatment.

Epidemiological evidence has shown that diabetes is associated with overt heart failure (HF) and worse clinical outcomes. However, the presence of a distinct primary diabetic cardiomyopathy (DCM) has not been easy to prove because the association between diabetes and HF is confounded by hypertension, obesity, microvascular dysfunction, and autonomic neuropathy. In addition, the molecular mechanisms underlying DCM are not yet fully understood, DCM usually remains asymptomatic in the early stage, and no specific biomarkers have been identified. Nonetheless, several mechanistic associations at the systemic, cardiac, and cellular/molecular levels explain different aspects of myocardial dysfunction, including impaired cardiac relaxation, compliance, and contractility. In this review, we focus on recent clinical and preclinical advances in our understanding of the molecular mechanisms of DCM and the role of anti-hyperglycemic agents in preventing DCM beyond their glucose lowering effect.

Diabetes (DM) patients have an increased risk (~50%) for sudden cardiac death (SCD), mostly as a result of ventricular arrhythmias. The molecular mechanisms involved remain partially defined. The potent proinflammatory lipid mediator leukotriene (LT) B4, is pathologically elevated in DM compared to nondiabetic patients, resulting in increased LTB4 accumulation in heart, leading to an increased risk for life-threatening proarrhythmic signatures. We used electrophysiology, immunofluorescence, and confocal microscopy approaches to evaluate LTB4 cellular effects in guinea pig heart and ventricular myocytes. We have observed that LTB4 is increased in multiple mouse models (C57BL/6 J/Lepob/ob and PANIC-ATTAC) of DM, promotes profound cellular arrhythmogenesis (spontaneous beats and early after depolarizations, EADs), and severely depresses the rapidly activating delayed rectifier K current (hERG1/IKr) density in HEK293 cells and guinea pig ventricular myocytes. We have further found that guinea pigs challenged with LTB4 displayed a significantly prolonged QT interval, and that this can be prevented with LTB4R inhibition, suggesting that preventing such LTB4R effects may be therapeutically beneficial in DM. Our data suggests that a further elucidation of LTB4 vulnerable substrates, and how this leads to ventricular arrhythmias, is likely to lead to continued improvements in management options, and the development of new therapies for prevention of SCD in DM patients.

Anthracyclines (ANTs) are widely used in cancer therapy, particularly for lymphoma, sarcoma, breast cancer, and childhood leukemia, and have become the cornerstone of chemotherapy for various malignancies. However, it is associated with fatal and dose-dependent cardiovascular complications, especially cardiotoxicity. Mitochondrial quality control mechanisms, encompassing mitophagy, mitochondrial dynamics, and mitochondrial biogenesis, maintain mitochondrial homeostasis in the cardiovascular system. Recent studies have highlighted that mitochondrial quality control mechanisms play considerable roles in ANTs-induced cardiotoxicity (AIC). In addition, natural products targeting mitochondrial quality control mechanisms have emerged as potential therapeutic strategies to alleviate AIC. This review summarizes the types, incidence, prevention, treatment, and pathomechanism of AIC, delves into the molecular mechanisms of mitochondrial quality control in the pathogenesis of AIC, and explores natural products that target these mechanisms, so as to provide potential targets and therapeutic drugs for address the clinical challenges in AIC prevention and treatment, where no effective medicines are available.

Heart failure with preserved ejection fraction (HFpEF) is increasing at an alarming rate worldwide, with limited effective therapeutic interventions in patients. Sudden cardiac death (SCD) and ventricular arrhythmias present substantial risks for the prognosis of these patients. Obesity is a risk factor for HFpEF and life-threatening arrhythmias. Obesity and its associated metabolic dysregulation, leading to metabolic syndrome, are an epidemic that poses a significant public health problem. More than one-third of the world population is overweight or obese, leading to an enhanced risk of incidence and mortality due to cardiovascular disease (CVD). Obesity predisposes patients to atrial fibrillation and ventricular and supraventricular arrhythmias-conditions that are caused by dysfunction in the electrical activity of the heart. To date, current therapeutic options for the cardiomyopathy of obesity are limited, suggesting that there is considerable room for the development of therapeutic interventions with novel mechanisms of action that will help normalize sinus rhythms in obese patients. Emerging candidates for modulation by obesity are cardiac ion channels and Ca-handling proteins. However, the underlying molecular mechanisms of the impact of obesity on these channels and Ca-handling proteins remain incompletely understood. Obesity is marked by the accumulation of adipose tissue, which is associated with a variety of adverse adaptations, including dyslipidemia (or abnormal systemic levels of free fatty acids), increased secretion of proinflammatory cytokines, fibrosis, hyperglycemia, and insulin resistance, which cause electrical remodeling and, thus, predispose patients to arrhythmias. Furthermore, adipose tissue is also associated with the accumulation of subcutaneous and visceral fat, which is marked by distinct signaling mechanisms. Thus, there may also be functional differences in the effects of the regional distribution of fat deposits on ion channel/Ca-handling protein expression. Evaluating alterations in their functional expression in obesity will lead to progress in the knowledge of the mechanisms responsible for obesity-related arrhythmias. These advances are likely to reveal new targets for pharmacological modulation. Understanding how obesity and related mechanisms lead to cardiac electrical remodeling is likely to have a significant medical and economic impact. Nevertheless, substantial knowledge gaps remain regarding HFpEF treatment, requiring further investigations to identify potential therapeutic targets. The objective of this study is to review cardiac ion channel/Ca-handling protein remodeling in the predisposition to metabolic HFpEF and arrhythmias. This review further highlights interleukin-6 (IL-6) as a potential target, cardiac bridging integrator 1 (cBIN1) as a promising gene therapy agent, and leukotriene B4 (LTB4) as an underappreciated pathway in future HFpEF management.

As a mechanism of cell death, ferroptosis has gained popularity since 2012. The process is distinguished by iron toxicity and phospholipid accumulation, in contrast to autophagy, apoptosis, and other cell death mechanisms. It is implicated in the advancement of multiple diseases across the body. Researchers currently know that osteosarcoma, osteoporosis, and other orthopedic disorders are caused by NRF2, GPX4, and other ferroptosis star proteins. The effective relief of osteoarthritis symptoms from deterioration has been confirmed by clinical treatment with multiple ferroptosis inhibitors. At the same time, it should be reminded that the mechanisms involved in ferroptosis that regulate orthopedic diseases are not currently understood. In this manuscript, we present the discovery process of ferroptosis, the mechanisms involved in ferroptosis, and the role of ferroptosis in a variety of orthopedic diseases. We expect that this manuscript can provide a new perspective on clinical diagnosis and treatment of related diseases.

Ketone bodies are molecules produced from fatty acids in the liver that act as energy carriers to peripheral tissues when glucose levels are low. Carbohydrate- and calorie-restricted diets, known to increase the levels of circulating ketone bodies, have attracted significant attention in recent years due to their potential health benefits in several diseases. Specifically, increasing ketones through dietary modulation has been reported to be beneficial for cardiovascular health and to improve glucose homeostasis and insulin resistance. Interestingly, although excessive production of ketones may lead to life-threatening ketoacidosis in diabetic patients, mounting evidence suggests that modest levels of ketones play adaptive and beneficial roles in pancreatic beta cells, although the exact mechanisms are still unknown. Of note, Sodium-Glucose Transporter 2 (SGLT2) inhibitors have been shown to increase the levels of beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body, which may play a pivotal role in mediating some of their protective effects in cardiovascular health and diabetes. This systematic review provides a comprehensive overview of the scientific literature and presents an analysis of the effects of ketone bodies on cardiovascular pathophysiology and pancreatic beta cell function. The evidence from both preclinical and clinical studies indicates that exogenous ketones may have significant beneficial effects on both cardiomyocytes and pancreatic beta cells, making them intriguing candidates for potential cardioprotective therapies and to preserve beta cell function in patients with diabetes.

Anticancer chemotherapy (ACT) remains a cornerstone in cancer treatment, despite significant advances in pharmacology over recent decades. However, its associated side effect toxicity continues to pose a major concern for both oncology clinicians and patients, significantly impacting treatment protocols and patient quality of life. Current clinical strategies to mitigate ACT-induced toxicity have proven largely unsatisfactory, leaving a critical unmet need to block toxicity mechanisms without diminishing ACT's therapeutic efficacy. This review aims to document the molecular mechanisms underlying ACT toxicity and highlight research efforts exploring the protective effects of trace elements (TEs) and their nanoparticles (NPs) against these mechanisms. Our literature review reveals that the primary driver of ACT toxicity is redox imbalance, which triggers oxidative inflammation, apoptosis, endoplasmic reticulum stress, mitochondrial dysfunction, autophagy, and dysregulation of signaling pathways such as PI3K/mTOR/Akt. Studies suggest that TEs, including zinc, selenium, boron, manganese, and molybdenum, and their NPs, can potentially counteract ACT-induced toxicity by inhibiting oxidative stress-mediated pathways, including NF-κB/TLR4/MAPK/NLRP3, STAT-3/NLRP3, Bcl-2/Bid/p53/caspases, and LC3/Beclin-1/CHOP/ATG6, while also upregulating protective signaling pathways like Sirt1/PPAR-γ/PGC-1α/FOXO-3 and Nrf2/HO-1/ARE. However, evidence regarding the roles of lncRNA and the Wnt/β-catenin pathway in ACT toxicity remains inconsistent, and the impact of TEs and NPs on ACT efficacy is not fully understood. Further research is needed to confirm the protective effects of TEs and their NPs against ACT toxicity in cancer patients. In summary, TEs and their NPs present a promising avenue as adjuvant agents for preventing non-target organ toxicity induced by ACT.