Role of gut microbiota in doxorubicin-induced cardiotoxicity: from pathogenesis to related interventions.

Doxorubicin (DOX) is a broad-spectrum and highly efficient anticancer agent, but its clinical implication is limited by lethal cardiotoxicity. Growing evidences have shown that alterations in intestinal microbial composition and function, namely dysbiosis, are closely linked to the progression of DOX-induced cardiotoxicity (DIC) through regulating the gut-microbiota-heart (GMH) axis. The role of gut microbiota and its metabolites in DIC, however, is largely unelucidated. Our review will focus on the potential mechanism between gut microbiota dysbiosis and DIC, so as to provide novel insights into the pathophysiology of DIC. Furthermore, we summarize the underlying interventions of microbial-targeted therapeutics in DIC, encompassing dietary interventions, fecal microbiota transplantation (FMT), probiotics, antibiotics, and natural phytochemicals. Given the emergence of microbial investigation in DIC, finally we aim to point out a novel direction for future research and clinical intervention of DIC, which may be helpful for the DIC patients.

Ferroptosis inhibitor alleviates sorafenib-induced cardiotoxicity by attenuating KLF11-mediated FSP1-dependent ferroptosis.

Sorafenib is a standard first-line drug for advanced hepatocellular carcinoma, but the serious cardiotoxic effects restrict its therapeutic applicability. Here, we show that iron-dependent ferroptosis plays a vital role in sorafenib-induced cardiotoxicity. Remarkably, our in vivo and in vitro experiments demonstrated that ferroptosis inhibitor application neutralized sorafenib-induced heart injury. By analyzing transcriptome profiles of adult human sorafenib-treated cardiomyocytes, we found that Krüppel-like transcription factor 11 (KLF11) expression significantly increased after sorafenib stimulation. Mechanistically, KLF11 promoted ferroptosis by suppressing transcription of ferroptosis suppressor protein 1 (FSP1), a seminal breakthrough due to its ferroptosis-repressing properties. Moreover, FSP1 knockdown showed equivalent results to glutathione peroxidase 4 (GPX4) knockdown, and FSP1 overexpression counteracted GPX4 inhibition-induced ferroptosis to a substantial extent. Cardiac-specific overexpression of FSP1 and silencing KLF11 by an adeno-associated virus serotype 9 markedly improved cardiac dysfunction in sorafenib-treated mice. In summary, FSP1-mediated ferroptosis is a crucial mechanism for sorafenib-provoked cardiotoxicity, and targeting ferroptosis may be a promising therapeutic strategy for alleviating sorafenib-induced cardiac damage.

Detailed analysis of metastatic colorectal cancer patients who developed cardiotoxicity on another fluoropyrimidine and switched to S-1 treatment (subgroup analysis of the CardioSwitch-study).

BACKGROUND AND PURPOSE: The CardioSwitch-study demonstrated that patients with solid tumors who develop cardiotoxicity on capecitabine or 5-fluorouracil (5-FU) treatment can be safely switched to S-1, an alternative fluoropyrimidine (FP). In light of the European Medicines Agency approval of S-1 in metastatic colorectal cancer (mCRC), this analysis provides more detailed safety and efficacy information, and data regarding metastasectomy and/or local ablative therapy (LAT), on the mCRC patients from the original study. MATERIALS AND METHODS: This retrospective cohort study was conducted at 12 European centers. The primary endpoint was recurrence of cardiotoxicity after switch. For this analysis, safety data are reported for 78 mCRC patients from the CardioSwitch cohort (N = 200). Detailed efficacy and outcomes data were available for 66 mCRC patients. RESULTS: Data for the safety of S-1 in mCRC patients were similar to the original CardioSwitch cohort and that expected for FP-based treatment, with no new concerns. Recurrent cardiotoxicity (all grade 1) with S-1-based treatment occurred in 4/78 (5%) mCRC patients; all were able to complete FP treatment. Median progression-free survival from initiation of S-1-based treatment was 9.0 months and median overall survival 26.7 months. Metastasectomy and/or LAT was performed in 33/66 (50%) patients, and S-1 was successfully used in recommended neoadjuvant/conversion or adjuvant-like combination regimens and schedules as for standard FPs. INTERPRETATION: S-1 is a safe and effective FP alternative when mCRC patients are forced to discontinue 5-FU or capecitabine due to cardiotoxicity and can be safely used in the standard recommended regimens, settings, and schedules.

Evaluation of time-to-onset and outcome of cardiac adverse events related to pembrolizumab using post-marketing surveillance in Japanese patients.

BACKGROUND: Pembrolizumab has been widely used in patients since its release, but information on cardiac Adverse Events (AEs) related to pembrolizumab remains lacking, particularly in Japanese populations. OBJECTIVES: This study aims to evaluate time to onset, incidence rates, and outcomes for pembrolizumab-induced cardiac AEs in patients with cancer using the Japanese Adverse Drug Event Report database. METHODS: We analysed data for the period from April 2004 to March 2022. Data on cardiac AEs were extracted and relative risks of AEs were estimated using the reporting odds ratio. RESULTS: We analysed 2,021,907 reports and identified 15,306 reports of AEs caused by pembrolizumab. Of these, 399 cardiac AEs were associated with pembrolizumab. Signals were detected for six cardiac AEs: myocarditis, immune-mediated myocarditis, pericardial effusion, cardiac tamponade, pericarditis, and pericarditis malignant. A histogram of median times to onset showed occurrence from 33 (21-97) days for immune-mediated myocarditis to 138 (67-168) days for pericarditis malignant, but some cases occurred even more than 1 year after the start of administration. Among these, myocarditis was the most frequently reported (27.1%), with fatal cases also reported. CONCLUSION: This study focused on cardiac AEs caused by pembrolizumab as post-marketing AEs. Patients should be monitored not only at the time of administration, but also over time for signs of these AEs, especially myocarditis, as some patients may have serious outcomes.

Association between Statin Use and Chemotherapy-Induced Cardiotoxicity: A Meta-Analysis.

Background: Chemotherapy-induced cardiac dysfunction (CIC) is a significant and concerning complication observed among cancer patients. Despite the demonstrated cardioprotective benefits of statins in various cardiovascular diseases, their effectiveness in mitigating CIC remains uncertain. Objective: This meta-analysis aims to comprehensively evaluate the potential cardioprotective role of statins in patients with CIC. Methods: A systematic literature search was conducted using PubMed, Embase, and Scopus databases to identify relevant articles published from inception until 10th May 2023. The outcomes were assessed using pooled odds ratio (OR) for categorical data and mean difference (MD) for continuous data, with corresponding 95% confidence intervals (95% CIs). Results: This meta-analysis comprised nine studies involving a total of 5532 patients, with 1904 in the statin group and 3628 in the non-statin group. The pooled analysis of primary outcome shows that patients who did not receive statin suffer a greater decline in the LVEF after chemotherapy compared to those who receive statin (MD, 3.55 (95% CI: 1.04-6.05), p = 0.01). Likewise, we observed a significantly higher final mean LVEF among chemotherapy patients with statin compared to the non-statin group of patients (MD, 2.08 (95% CI: 0.86-3.30), p > 0.001). Additionally, there was a lower risk of incident heart failure in the statin group compared to the non-statin group of patients (OR, 0.41 (95% CI: 0.27-0.62), p < 0.001). Lastly, the change in the mean difference for LVEDV was not statistically significant between the statin and non-statin groups (MD, 1.55 (95% CI: -5.22-8.33), p = 0.65). Conclusion: Among patients of CIC, statin use has shown cardioprotective benefits by improving left ventricular function and reducing the risk of heart failure.

The NEDD8 activating enzyme inhibitor MLN4924 mitigates doxorubicin-induced cardiotoxicity in mice.

Doxorubicin (DOX) is a widely utilized chemotherapeutic agent in clinical oncology for treating various cancers. However, its clinical use is constrained by its significant side effects. Among these, the development of cardiomyopathy, characterized by cardiac remodeling and eventual heart failure, stands as a major concern following DOX chemotherapy. In our current investigation, we have showcased the efficacy of MLN4924 in mitigating doxorubicin-induced cardiotoxicity through direct inhibition of the NEDD8-activating enzyme, NAE. MLN4924 demonstrated the ability to stabilize mitochondrial function post-doxorubicin treatment, diminish cardiomyocyte apoptosis, alleviate oxidative stress-induced damage in the myocardium, enhance cardiac contractile function, mitigate cardiac fibrosis, and impede cardiac remodeling associated with heart failure. At the mechanistic level, MLN4924 intervened in the neddylation process by inhibiting the NEDD8 activating enzyme, NAE, within the murine cardiac tissue subsequent to doxorubicin treatment. This intervention resulted in the suppression of NEDD8 protein expression, reduction in neddylation activity, and consequential manifestation of cardioprotective effects. Collectively, our findings posit MLN4924 as a potential therapeutic avenue for mitigating doxorubicin-induced cardiotoxicity by attenuating heightened neddylation activity through NAE inhibition, thereby offering a viable and promising treatment modality for afflicted patients.

Precision Cardio-oncology: Update on Omics-Based Diagnostic Methods.

OPINION STATEMENT: Cardio-oncology is an emerging interdisciplinary field dedicated to the early detection and treatment of adverse cardiovascular events associated with anticancer treatment, and current clinical management of anticancer-treatment-related cardiovascular toxicity (CTR-CVT) remains limited by a lack of detailed phenotypic data. However, the promise of diagnosing CTR-CVT using deep phenotyping has emerged with the development of precision medicine, particularly the use of omics-based methodologies to discover sensitive biomarkers of the disease. In the future, combining information produced by a variety of omics methodologies could expand the clinical practice of cardio-oncology. In this review, we demonstrate how omics approaches can improve our comprehension of CTR-CVT deep phenotyping, discuss the positive and negative aspects of available omics approaches for CTR-CVT diagnosis, and outline how to integrate multiple sets of omics data into individualized monitoring and treatment. This will offer a reliable technical route for lowering cardiovascular morbidity and mortality in cancer patients and survivors.

Role of mitochondria in doxorubicin-mediated cardiotoxicity: from molecular mechanisms to therapeutic strategies.

This comprehensive review delves into the pivotal role of mitochondria in doxorubicin-induced cardiotoxicity, a significant complication limiting the clinical use of this potent anthracycline chemotherapeutic agent. Doxorubicin, while effective against various malignancies, is associated with dose-dependent cardiotoxicity, potentially leading to irreversible cardiac damage. The review meticulously dissects the molecular mechanisms underpinning this cardiotoxicity, particularly focusing on mitochondrial dysfunction, a central player in this adverse effect. Central to the discussion is the concept of mitochondrial quality control (MQC), including mitochondrial dynamics (fusion/fission balance) and mitophagy. The review presents evidence linking aberrations in these processes to cardiotoxicity in doxorubicin-treated patients. It elucidates how doxorubicin disrupts mitochondrial dynamics, leading to an imbalance between mitochondrial fission and fusion, and impairs mitophagy, culminating in the accumulation of dysfunctional mitochondria and subsequent cardiac cell damage. Furthermore, the review explores emerging therapeutic strategies targeting mitochondrial dysfunction. It highlights the potential of modulating mitochondrial dynamics and enhancing mitophagy to mitigate doxorubicin-induced cardiac damage. These strategies include pharmacological interventions with mitochondrial fission inhibitors, fusion promoters, and agents that modulate mitophagy. The review underscores the promising results from preclinical studies while advocating for more extensive clinical trials to validate these approaches in human patients. In conclusion, this review offers valuable insights into the intricate relationship between mitochondrial dysfunction and doxorubicin-mediated cardiotoxicity. It underscores the need for continued research into targeted mitochondrial therapies as a means to improve the cardiac safety profile of doxorubicin, thereby enhancing the overall treatment outcomes for cancer patients.

Doxorubicin, doxorubicinol, cardiotoxicity, breast cancer, volumetric absorptive microsampling, LC-MS/MS.

<b>Background and Objective:</b> Doxorubicin is an anticancer therapy belonging to the anthracycline class, which has clinical activity in breast cancer. Doxorubicin can cause cardiotoxic effects due to the formation of doxorubicinol as its main metabolite. The purpose of this study was to obtain the optimum sample preparation conditions for the analysis of doxorubicin in VAMS and as a form of therapeutic drug monitoring (TDM) in patients with cancer breasts. <b>Materials and Methods:</b> Analyze doxorubicin and doxorubicinol levels with Volumetric Absorptive Microsampling (VAMS) in patients' cancer breasts receiving doxorubicin in their therapeutic regimen. The sample was analyzed using Ultra Performance Liquid Chromatography tandem Mass Spectrometry (LC-MS/MS). The method uses deep linear range concentrations of 8-200 ng/mL for doxorubicin and 3-100 ng/mL for doxorubicinol. <b>Results:</b> Multiple reaction monitoring (MRM) value set at m/z 544.22>396.9 for doxorubicin; m/z 546.22>398.9 for doxorubicinol and m/z 528.5>362.95 for daunorubicin. The LLOQ value obtained was 8 ng/mL for doxorubicin and 3 ng/mL for doxorubicinol with linearity of 0.9904 for doxorubicin and 0.9902 for doxorubicinol. Analysis results show doxorubicin levels were in the range of 9.47 ng/mL to 87.84 ng/mL and doxorubicinol range between 4.24 and 54.02 ng/mL. <b>Conclusion:</b> Dosage cumulative doxorubicin ranges between 47.93 and 346.09 mg/m²; with this, the risk of cardiomyopathy in the patients surveyed is under 4%, according to the literature.

Protective effects of arbutin against doxorubicin-induced cardiac damage.

BACKGROUND: Doxorubicin is an effective antineoplastic agent but has limited clinical application because of its cumulative toxicities, including cardiotoxicity. Cardiotoxicity causes lipid peroxidation, genetic impairment, oxidative stress, inhibition of autophagy, and disruption of calcium homeostasis. Doxorubicin-induced cardiotoxicity is frequently tried to be mitigated by phytochemicals, which are derived from plants and possess antioxidant, anti-inflammatory, and anti-apoptotic properties. Arbutin, a natural antioxidant found in the leaves of the bearberry plant, has numerous pharmacological benefits, including antioxidant, anti-bacterial, anti-hyperglycemic, anti-inflammatory, and anti-tumor activity. METHODS AND RESULTS: The study involved male Wistar rats divided into three groups: a control group, a group treated with doxorubicin (20 mg/kg) to induce cardiac toxicity, a group treated with arbutin (100 mg/kg) daily for two weeks before doxorubicin administration. After treatment, plasma and heart tissue samples were collected for analysis. The samples were evaluated for oxidative stress parameters, including superoxide dismutase, malondialdehyde, and catalase, as well as for cardiac biomarkers, including CK, CK-MB, and LDH. The heart tissues were also analyzed using molecular (TNF-α, IL-1ß and Caspase 3), histopathological and immunohistochemical methods (8-OHDG, 4 Hydroxynonenal, and dityrosine). The results showed that arbutin treatment was protective against doxorubicin-induced oxidative damage by increasing SOD and CAT activity and decreasing MDA level. Arbutin treatment was similarly able to reverse the inflammatory response caused by doxorubicin by reducing TNF-α and IL-1ß levels and also reverse the apoptosis by decreasing caspase-3 levels. It was able to prevent doxorubicin-induced cardiac damage by reducing cardiac biomarkers CK, CK-MB and LDH levels. In addition to all these results, histopathological analyzes also show that arbutin may be beneficial against the damage caused by doxorubicin on heart tissue. CONCLUSION: The study suggests that arbutin has the potential to be used to mitigate doxorubicin-induced cardiotoxicity in cancer patients.

Left atrial reservoir longitudinal strain and its incremental value to the left ventricular global longitudinal strain in predicting anthracycline-induced cardiotoxicity.

BACKGROUND: Left ventricular global longitudinal strain (LVGLS) has been recommended by current guidelines for diagnosing anthracycline-induced cardiotoxicity. However, little is known about the early changes in left atrial (LA) morphology and function in this population. Our study aimed to evaluate the potential usefulness of LA indices and their incremental value to LVGLS with three-dimensional echocardiography (3DE) in the early detection of subclinical cardiotoxicity in patients with lymphoma receiving anthracycline. METHODS: A total of 80 patients with diffuse large B-cell lymphoma who received six cycles of anthracycline-based treatment were enrolled. Echocardiography was performed at baseline (T0), after four cycles (T1), and after the completion of six cycles of chemotherapy (T2). Left ventricular ejection fraction (LVEF), LVGLS, LA volumes, LA emptying fraction (LAEF), LA active emptying fraction (LAAEF), and LA reservoir longitudinal strain (LASr) were quantified with 3DE. Left atrioventricular global longitudinal strain (LAVGLS) was calculated as the sum of peak LASr and the absolute value of peak LVGLS (LAVGLS = LASr+|LVGLS|). LV cardiotoxicity was defined as a new LVEF reduction by ≥10 percentage points to an LVEF of ≤50%. RESULTS: Fourteen (17.5%) patients developed LV cardiotoxicity at T2. LA volumes, LAEF, and LAAEF remained stable over time. Impairment of LASr (28.35 ± 5.03 vs. 25.04 ± 4.10, p < .001), LVGLS (-22.77 ± 2.45 vs. -20.44 ± 2.62, p < .001), and LAVGLS (51.12 ± 5.63 vs. 45.61 ± 5.22, p < .001) was observed by the end of the fourth cycle of chemotherapy (T1). Statistically significant declines in LVEF (61.30 ± 4.73 vs. 57.08 ± 5.83, p < .001) were only observed at T2. The relative decrease in LASr (ΔLASr), LVGLS (ΔLVGLS), and LAVGLS (ΔLAVGLS) from T0 to T1 were predictors of LV cardiotoxicity. A ΔLASr of >19.75% (sensitivity, 71.4%; specificity, 87.9%; area under the curve (AUC), .842; p < .001), a ΔLVGLS of >13.19% (sensitivity, 78.6%; specificity, 74.2%; AUC, .763; p < .001), and a ΔLAVGLS of >16.80% (sensitivity, 78.6%; specificity, 93.9%; AUC, .905; p < .001) predicted subsequent LV cardiotoxicity at T2, with the AUC of ΔLAVGLS significantly larger than that of ΔLVGLS (.905 vs. .763, p = .027). Compared to ΔLVGLS, ΔLAVGLS showed improved specificity (93.9% vs. 74.2%, p = .002) and maintained sensitivity in predicting LV cardiotoxicity. CONCLUSIONS: LASr could predict anthracycline-induced LV cardiotoxicity with excellent diagnostic performance. Incorporating LASr into LVGLS (LAVGLS) led to a significantly improved specificity and maintained sensitivity in predicting LV cardiotoxicity.

AP39, a novel mitochondria-targeted hydrogen sulfide donor ameliorates doxorubicin-induced cardiotoxicity by regulating the AMPK/UCP2 pathway.

Doxorubicin (DOX) is a broad-spectrum, highly effective antitumor agent; however, its cardiotoxicity has greatly limited its use. Hydrogen sulfide (H2S) is an endogenous gaseous transmitter that exerts cardioprotective effects via the regulation of oxidative stress and apoptosis and maintenance of mitochondrial function, among other mechanisms. AP39 is a novel mitochondria-targeted H2S donor that, at appropriate concentrations, attenuates intracellular oxidative stress damage, maintains mitochondrial function, and ameliorates cardiomyocyte injury. In this study, DOX-induced cardiotoxicity models were established using H9c2 cells and Sprague-Dawley rats to evaluate the protective effect of AP39 and its mechanisms of action. Both in vivo and in vitro experiments showed that DOX induces oxidative stress injury, apoptosis, and mitochondrial damage in cardiomyocytes and decreases the expression of p-AMPK/AMPK and UCP2. All DOX-induced changes were attenuated by AP39 treatment. Furthermore, the protective effect of AP39 was significantly attenuated by the inhibition of AMPK and UCP2. The results suggest that AP39 ameliorates DOX-induced cardiotoxicity by regulating the expression of AMPK/UCP2.

Protective Role of Dioscin against Doxorubicin-Induced Chronic Cardiotoxicity: Insights from Nrf2-GPX4 Axis-Mediated Cardiac Ferroptosis.

Recent evidence suggests that ferroptosis, an iron-facilitated cell death with excessive lipid peroxidation, is a critical mechanism underlying doxorubicin (DOX)-induced cardiotoxicity (DIC). Although dioscin has been reported to improve acute DIC, direct evidence is lacking to clarify the role of dioscin in chronic DIC and its potential mechanism in cardiac ferroptosis. In this study, we used chronic DIC rat models and H9c2 cells to investigate the potential of dioscin to mitigate DIC by inhibiting ferroptosis. Our results suggest that dioscin significantly improves chronic DIC-induced cardiac dysfunction. Meanwhile, it significantly inhibited DOX-induced ferroptosis by reducing Fe2+ and lipid peroxidation accumulation, maintaining mitochondrial integrity, increasing glutathione peroxidase 4 (GPX4) expression, and decreasing acyl-CoA synthetase long-chain family 4 (ACSL4) expression. Through transcriptomic analysis and subsequent validation, we found that the anti-ferroptotic effects of dioscin are achieved by regulating the nuclear factor-erythroid 2-related factor 2 (Nrf2)/GPX4 axis and Nrf2 downstream iron metabolism genes. Dioscin further downregulates nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and upregulates expression of frataxin (FXN) and ATP-binding cassette B8 (ABCB8) to limit mitochondrial Fe2+ and lipid peroxide accumulation. However, Nrf2 inhibition diminishes the anti-ferroptotic effects of dioscin, leading to decreased GPX4 expression and increased lipid peroxidation. This study is a compelling demonstration that dioscin can effectively reduce DIC by inhibiting ferroptosis, which is dependent on the Nrf2/GPX4 pathway modulation.

Doxorubicin conjugates: a practical approach for its cardiotoxicity alleviation.

INTRODUCTION: Doxorubicin (DOX) emerges as a cornerstone in the arsenal of potent chemotherapeutic agents. Yet, the clinical deployment of DOX is tarnished by its proclivity to induce severe cardiotoxic effects, culminating in heart failure and other consequential morbidities. In response, a panoply of strategies has undergone rigorous exploration over recent decades, all aimed at attenuating DOX's cardiotoxic impact. The advent of encapsulating DOX within lipidic or polymeric nanocarriers has yielded a dual triumph, augmenting DOX's therapeutic efficacy while mitigating its deleterious side effects. AREAS COVERED: Recent strides have spotlighted the emergence of DOX conjugates as particularly auspicious avenues for ameliorating DOX-induced cardiotoxicity. These conjugates entail the fusion of DOX through physical or chemical bonds with diminutive natural or synthetic moieties, polymers, biomolecules, and nanoparticles. This spectrum encompasses interventions that impinge upon DOX's cardiotoxic mechanism, modulate cellular uptake and localization, confer antioxidative properties, or refine cellular targeting. EXPERT OPINION: The endorsement of DOX conjugates as a compelling stratagem to mitigate DOX-induced cardiotoxicity resounds from this exegesis, amplifying safety margins and the therapeutic profile of this venerated chemotherapeutic agent. Within this ambit, DOX conjugates stand as a beacon of promise in the perpetual pursuit of refining chemotherapy-induced cardiac compromise.

Semaglutide attenuates doxorubicin-induced cardiotoxicity by ameliorating BNIP3-Mediated mitochondrial dysfunction.

AIMS: Doxorubicin is a powerful chemotherapeutic agent for cancer, whose use is limited due to its potential cardiotoxicity. Semaglutide (SEMA), a novel analog of glucagon-like peptide-1 (GLP-1), has received widespread attention for the treatment of diabetes. However, increasing evidence has highlighted its potential therapeutic benefits on cardiac function. Therefore, the objective of this study was to examine the efficacy of semaglutide in ameliorating doxorubicin-induced cardiotoxicity. METHODS AND RESULTS: Doxorubicin-induced cardiotoxicity is an established model to study cardiac function. Cardiac function was studied by transthoracic echocardiography and invasive hemodynamic monitoring. The results showed that semaglutide significantly ameliorated doxorubicin-induced cardiac dysfunction. RNA sequencing suggested that Bnip3 is the candidate gene that impaired the protective effect of semaglutide in doxorubicin-induced cardiotoxicity. To determine the role of BNIP3 on the effect of semaglutide in doxorubicin-induced cardiotoxicity, BNIP3 with adeno-associated virus serotype 9 (AAV9) expressing cardiac troponin T (cTnT) promoter was injected into tail vein of C57/BL6J mice to overexpress BNIP3, specifically in the heart. Overexpression of BNIP3 prevented the improvement in cardiac function caused by semaglutide. In vitro experiments showed that semaglutide, via PI3K/AKT pathway, reduced BNIP3 expression in the mitochondria, improving mitochondrial function. CONCLUSION: Semaglutide ameliorates doxorubicin-induced mitochondrial and cardiac dysfunction via PI3K/AKT pathway, by reducing BNIP3 expression in mitochondria. The improvement in mitochondrial function reduces doxorubicin-mediated cardiac injury and improves cardiac function. Therefore, semaglutide is a potential therapy to reduce doxorubicin-induced acute cardiotoxicity.

Inhibition of METTL3 ameliorates doxorubicin-induced cardiotoxicity through suppression of TFRC-mediated ferroptosis.

BACKGROUND: Doxorubicin (DOX) is a chemotherapeutic drug, while its clinical use is greatly limited by the life-threatening cardiotoxicity. N6-methyladenosine (m6A) RNA modification participates in varieties of cellular processes. Nonetheless, it remains elusive whether m6A modification and its methyltransferase METTL3 are involved in the progression of DOX-induced cardiotoxicity (DIC). METHODS: Mice were administrated with DOX (accumulative dosage of 20 mg/kg) repeatedly to establish a chronic DIC model. Cardiomyocyte-specific conditional METTL3 knockout mice were employed to evaluate the effects of altered m6A RNA modification on DIC. The effects of METTL3 on cardiomyocyte ferroptosis were also examined in response to DOX stimulation. RESULTS: DOX led to increased levels in m6A modification and METTL3 expression in cardiomyocytes in a c-Jun-dependent manner. METTL3-knockout mice exhibited improved cardiac function, remodeling and injury following DOX insult. Besides, inhibition of METTL3 alleviated DOX-induced iron accumulation and ferroptosis in cardiomyocytes, whereas METTL3 overexpression exerted the opposite effects. Mechanistically, METTL3 promoted m6A modification of TFRC mRNA, a critical gene governing iron uptake, and enhanced its stability through recognition of the m6A reader protein, IGF2BP2. Moreover, pharmacological administration of a highly selective METTL3 inhibitor STM2457 effectively ameliorated DIC in mice. CONCLUSION: METTL3 plays a cardinal role in the etiology of DIC by regulating cardiac iron metabolism and ferroptosis through TFRC m6A modification. Inhibition of METTL3 might be a potential therapeutic avenue for DIC.

Evaluation of aconitine cardiotoxicity with a heart-on-a-particle prepared by a microfluidic device.

A heart-on-a-particle model based on multicompartmental microgel is proposed to simulate the heart microenvironment and study the cardiotoxicity of drugs. The relevant microgel was fabricated by a biocompatible microfluidic-based approach, where heart function-related HL-1 and HUVEC cells were arranged in separate compartments. Finally, the mechanism of aconitine-induced heart toxicity was elucidated using mass spectrometry and molecular biotechnology.

Doxorubicin induces phosphorylation of lamin A/C and loss of nuclear membrane integrity: A novel mechanism of cardiotoxicity.

Lamin A/C, essential inner nuclear membrane proteins, have been linked to progeria, a disease of accelerated aging, and many other diseases, which include cardiac disorder. Lamin A/C mutation and its phosphorylation are associated with altering nuclear shape and size. The role of lamin A/C in regulating normal cardiac function was reported earlier. In the present study, we hypothesized that Doxorubicin (Dox) may alter total lamin A/C expression and phosphorylation, thereby taking part in cardiac injury. An in vitro cellular injury model was generated with Dox (0.1-10.0 µM) treatment on cardiomyoblast cells (H9c2) to prove our hypothesis. Increased size and irregular (ameboid) nucleus shape were observed in H9c2 cells after Dox treatment. Similarly, we have observed a significant increase in cell death on increasing the Dox concentration. The expression of lamin A/C and its phosphorylation at serine 22 significantly decreased and increased, respectively in H9c2 cells and rat hearts after Dox exposure. Phosphorylation led to depolymerization of the lamin A/C in the inner nuclear membrane and was evidenced by their presence throughout the nucleoplasm as observed by immunocytochemistry techniques. Thinning and perforation on the walls of the nuclear membrane were observed in Dox-treated H9c2 cells. LMNA-overexpression in H9c2 protected the cells from Dox-induced cell death, reversing all changes described above. Further, improvement of lamin A/C levels was observed in Dox-treated H9c2 cells when treated with Purvalanol A, a CDK1 inhibitor and N-acetylcysteine, an antioxidant. The study provides new insight regarding Dox-induced cardiac injury with the involvement of lamin A/C and alteration of inner nuclear membrane structure.

PLCE1 enhances mitochondrial dysfunction to promote GSDME-mediated pyroptosis in doxorubicin-induced cardiotoxicity.

BACKGROUND: The therapeutic value and long-term application of doxorubicin (DOX) were hampered by its severe irreversible cardiotoxicity. Phospholipase C epsilon 1 (PLCE 1) was reported as a new member of the phospholipase C (PLC) family which controls the level of phosphoinositides in cells. Pyroptosis is a newly discovered inflammatory type of regulated cell death. Recent studies have consolidated that chemotherapeutic drugs lead to pyroptosis. Additionally, the phosphoinositide signaling system has remarkable effects on the execution of cell death. We aim to investigate the role of PLCE1 and the mechanism of pyroptosis from the context of DOX-induced cardiotoxicity. METHODS: In the current study, in vitro and in vivo experiments were performed to dissect the underlying mechanism of cardiomyocyte pyroptosis during DOX-induced cardiac injury. The molecular mechanism of PLCE1 was identified by the human cardiomyocyte AC16 cell line and C57BL/6 mouse model. RESULTS: The results here indicated that PLCE1 high expressed and pyroptotic cell death presented in cardiomyocytes after DOX application, which was negatively correlated to heart function. DOX-induced cell model disclosed pyroptosis mediated by Gasdermin E (GSDME) protein and involved in mitochondrial damage. Conversely, the deletion of PLCE1 ameliorated mitochondrial dysfunction by suppressing ROS accumulation and reversing mitochondrial membrane potential, and then increased cell viability effectively. More importantly, the in vivo experiment demonstrated that inhibition of PLCE1 reduced pyroptotic cell death and improved heart effect. CONCLUSIONS: We discovered firstly that PLCE1 inhibition protected cardiomyocytes from DOX-induced pyroptotic injury and promoted cardiac function. This information offers a theoretical basis for promising therapy.