Open research questions in Chemotherapy-induced cardiotoxicity and mitigation

What the literature leaves open

• Background Troponin monitoring is recommended for the early detection of immune checkpoint inhibitor (ICI)–associated myocarditis, but its utility as a universal screening tool for all cardiovascular (CV) toxic effects in patients with cancer treated with ICIs remains uncertain.

  Troponin Screening and Major Cardiovascular Adverse Events During Immune Checkpoint Inhibitor Therapy · 2026 · DOI

• Although studies have shown that AET delays tumor growth and cachexia in Walker-256 tumor-bearing rats, little is known about the impact of AET on cardiac phenotypes in different cancer models.

  Aerobic exercise training attenuates the deleterious effects of walker-256 cancer: effects on physical capacity, cachexia, and cardiac mass · 2026 · DOI

• While studies suggested that Huangqi Guizhi Wuwu Decoction (HGWD) can mitigate doxorubicin-induced cardiotoxicity (DIC), the specific mechanism of action remains unclear.

  Bioinformatics and network pharmacology to explore Huangqi Guizhi Wuwu Decoction in regulating mitophagy to ameliorate doxorubicin-induced cardiotoxicity the potential mechanism · 2026 · DOI

• Although 3D echo‑ cardiography has not yet been fully established in routine clinical practice in Japan due to the costs of introducing measurement software and equipment, its proactive use helps improve the accuracy of LVEF measurement.

  Practical guidance for echocardiography for cancer therapy-related cardiac dysfunction: 2026 focused update · 2026 · DOI

• Abstract Radiation‑induced afferent baroreflex failure (R‑ABF) is a highly morbid late effect of neck irradiation in head and neck cancer survivors, and is frequently underrecognized due to nonspecific, fluctuating symptoms.

  Targeted autonomic testing for radiation‑induced baroreflex failure in head and neck cancer survivors: index case and early program experience · 2026 · DOI

• Reported cumulative dose thresholds varied widely for idarubicin (150—450 mg/m 2 ) and mitoxantrone (80—250 mg/m 2 ); equivalence factors differed more than ten‑fold between institutions.

  Variability in anthracycline dose conversions and cardiotoxicity monitoring: insights from hospital pharmacists on institutional protocols in oncology practice · 2026 · DOI

• Current approaches to predict and prevent KI-induced cardiac adverse events (CAEs) are limited by an incomplete understanding of underlying mechanisms, including the contribution of off-target kinase engagement.

  Kinome profiling allows examination and prediction of kinase inhibitor cardiotoxicity · 2026 · DOI

• Despite these promising findings, this study has some limitations: ● A large sample size is recommended for future studies to ascertain generalization of results. ● Serum oxidative stress biomarkers (MDA, SOD, GPX) measured rather than their levels in cardiac tissue ho- mogenates may not fully reflect myocardial oxidative status. ● For definite demonstration of inflammation and cardiac apoptosis, serum NLrp3 alone isn’t enough to establish inflammasome activation in cardiac tissue. Future stud- ies should measure its tissue expression and downstream cytokines (IL-1β/IL-18) & caspase-1. ● The correlations should be interpreted as exploratory, hypothesis-generating findings and should be validated in larger studies. Author contributions Heba M. Galal and Sally A. Sayed conceived and designed research. Heba M. Galal, Elgamal DA, D M Raafat, As- maa M. Ismail, Sally A. Sayed conducted the experiments. Heba M. Galal and Marwa H. Bakr did statistical analysis of the data. Heba M. Galal, Marwa H. Bakr, Nahla M Elsherbiny and Sally A. Sayed wrote and revised the manuscript. All authors read and approved the manuscript. Funding The authors declare that there are no external official funds for this research, and the work is entirely funded by the authors. Data availability data is available on request. 1 3Journal of Molecular Histology (2026) 57:179 Declarations Competing interests The authors declare no competing interests.

  The possible effects of folic acid and postbiotic yeast on doxorubicin–induced cardiotoxicity in rats: interactions among the gut microbiota, antioxidants, and NLrp3 activities · 2026 · DOI

• Artificial intelligence–enhanced ECG interpretation, along with machine learning models that consider clinical factors, pharmacogenomic profiles, and longitudinal ECG data, could change risk assessment from static snapshots to dynamic, real-time forecasts. Incorporating genetic screening for hERG channel variants, congenital long QT syndrome alleles, and drug-metabolizing polymorphisms (such as CYP3A4 and KCNH2) before treatment would allow doctors to choose, dose, and monitor drugs in a way that lowers the risk of arrhythmia without compromising cancer control [120,121]. Ion channel safety profiling and computational cardiotoxicity modeling should be included in the early stages of oncology drug development to identify and remove drugs with high QTc liability before clinical harm occurs. On the clinical side, multi-institutional cardio-oncology registries linked to electronic health records and supported by wearable ECG-enabled biosensors can enable continuous outpatient monitoring, document rare arrhythmic events, and provide real-world evidence to improve risk classification [122–124]. These data should inform oncology-specific QTc monitoring protocols consistent with the guidelines from NCCN, ASCO, and ESC. These protocols should include tiered recommendations based on the patient’s drug exposure, comorbidities, and susceptibility. Future studies should evaluate interventional strategies, including preventive pacing for patients at high risk of recurring TdP, electrolyte-stabilizing adjuncts, and cardioprotective therapies to keep high-risk patients safe without prematurely discontinuing effective cancer therapy. It is equally important to strengthen the educational infrastructure. For example, adding cardio-oncology and arrhythmia recognition modules to fellowship training, oncology curricula, and continuing medical education will ensure that doctors across many fields can spot and respond to early warning signs. The sector can move from reactive rescue to anticipatory prevention by combining new technologies, accurate risk prediction, and standardized treatment approaches. This will improve both cardiac safety and cancer outcomes. Strengths and Limitations of Our Study This narrative review has several important limitations. First, because it is not a systematic review, study identification and selection were not governed by a preregistered protocol, comprehensive search strategy, or duplicate screening. As a result, selection bias is possible, and relevant studies may have been missed while certain themes may be overrepresented.

  QT Prolongation and Arrhythmias in Cancer Therapy: A Narrative Review of Mechanistic and Clinical Studies · 2026 · DOI

• Several limitations warrant considered. First, the preclinical model uses a single age and sex (4-week-old female mice) to approximate an adolescent stage and does not capture the full age- and sex-related heterogeneity within the AYA population. Second, the miRNA analysis was conducted on a small sample size due to collection time point feasibility challenges (n=16). While our targeted analysis of miR-133b, miR-206, and miR-126 revealed consistent reductions post-Dox that were mitigated by exercise, comprehensive miRNA sequencing could further elucidate broader expression profiles altered by Dox therapy and exercise interventions. Such an approach might identify novel candidates involved in mitophagy, autophagy, or vascular repair pathways, providing deeper insights into the molecular mechanisms of Dox-induced muscle wasting and exercise-mediated protection. Future studies incorporating miRNA sequencing in both preclinical models and larger AYA cohorts will be essential to validate and expand these findings. Third, given that the present study was not designed to elucidate determinates of physical activity such as tumor burden or location, the influence of tumor burden and location should be considered potential confounding factors and controlled for in future larger scale investigations. Fourth, as the study focus was on AYAs diagnosed with sarcoma and the chemotherapeutic treatment doxorubicin, these findings may not be generalizable to AYAs with other cancer types or ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT receiving different chemotherapies. Moreover, skeletal muscle loss may vary based on tumor location and associated physical limitations which may impact activity levels. Although CT imaging fields containing the presence of local tumor were not used in the current study, we did not evaluate the influence of variable peripheral tumor location on skeletal muscle loss. Future studies should aim to address these gaps. Fifth, the translational gap between mouse treadmill exercise and human physical activity should be carefully considered. Additionally, the importance of considering sex as a biological variable in biomedical research has been emphasized in recent guidelines (62). Given that the present study utilized only female mice in accordance with our previously published model (8), future studies should investigate whether these findings are also seen in males. Sixth, individual skeletal muscle wet weights and cross-sectional area were not measured, as the study was designed to focus on histologic, ultrastructural, and molecular indicators of muscle injury.

  Potential biomarkers and preventative interventions for muscle wasting in adolescent and young adults with cancer: A translational study · 2026 · DOI

• However, despite increasing efforts to identify early predictors of cardiotoxicity and growing evidence of the importance of cardiac biomarkers for this purpose, large randomized multicenter clinical trials are still lacking and so there is still no scientific agreement on the best approach for early diagnosis.

  How to identify anthracycline-induced cardiotoxicity early and reduce its clinical impact in everyday practice · 2021 · DOI

• However, these attempts to continually improve local control through dose escalation, have met mixed results culminating in the findings of the RTOG trial 0617, where the heart dose was associated with a worse overall survival, indicating a significant contribution to radiation-induced cardiac morbidity.

  Cardiac toxicity of lung cancer radiotherapy · 2019 · DOI

• Unfortunately, its cytostatic effect in therapeutic doses is frequently insufficient; but the use of higher DOX doses is limited by the development of systemic toxicity, especially cardiotoxicity.

  Possibilities to increase the effectiveness of doxorubicin in cancer cells killing · 2011 · DOI

• Although substantial progress has been made in deciphering these mechanisms, the precise temporal sequence and reciprocal nature of cardiorenal injury remain to be fully defined.

  Anthracycline-induced cardiorenal toxicity: from molecular mechanisms to clinical management · 2026 · DOI

• In this comment, Gholami and O’Keefe‑McCarthy discuss cardiotoxicity‑induced heart failure and the need for further research into this…

  Cardiotoxicity-induced heart failure: a call for research · 2024 · DOI

• Heart dosimetric parameters are of great importance in developing a treatment plan, but few data are available regarding radiosensitivity and dose-volume constraints for specific heart structures.

  Cardiotoxicity of mediastinal radiotherapy · 2019 · DOI

Most-cited papers in Chemotherapy-induced cardiotoxicity and mitigation

• Immune Checkpoint Inhibitors and Cardiotoxicity: An Analysis of Spontaneous Reports in Eudravigilance · Drug Safety · 2021 · 73 citations
• Possibilities to increase the effectiveness of doxorubicin in cancer cells killing · Drug Metabolism Reviews · 2011 · 73 citations
• Cardiotoxicity of mediastinal radiotherapy · Reports of Practical Oncology & Radiotherapy · 2019 · 41 citations
• Cardiovascular Toxicity of Immune Checkpoint Inhibitors: A Guide for Clinicians · Drug Safety · 2023 · 36 citations
• Cardiotoxicity of radiation therapy in esophageal cancer · Reports of Practical Oncology & Radiotherapy · 2020 · 29 citations
• Cardiovascular Risks of Diclofenac Versus Other Older COX-2 Inhibitors (Meloxicam and Etodolac) and Newer COX-2 Inhibitors (Celecoxib and Etoricoxib): A Series of Nationwide Emulated Trials · Drug Safety · 2022 · 26 citations
• Montelukast ameliorates doxorubicin-induced cardiotoxicity via modulation of p-glycoprotein and inhibition of ROS-mediated TNF-α/NF-κB pathways · Drug and Chemical Toxicology · 2020 · 21 citations
• Cardiac toxicity of lung cancer radiotherapy · Reports of Practical Oncology & Radiotherapy · 2019 · 21 citations
• Anthracycline-induced cardiotoxicity prevention with angiotensin-converting enzyme inhibitor ramipril in women with low-risk breast cancer: results of a prospective randomized study · Kardiologia Polska · 2020 · 19 citations
• A practical approach to the 2022 ESC cardio-oncology guidelines: Comments by a team of experts – cardiologists and oncologists · Kardiologia Polska · 2023 · 17 citations

Most recent work

• Cellular crosstalk in doxorubicin-induced cardiotoxicity: underlying mechanisms and therapeutic strategies · Biochemical Pharmacology · 2026
• Practical guidance for echocardiography for cancer therapy-related cardiac dysfunction: 2026 focused update · Journal of Echocardiography · 2026
• Molecular insights into doxorubicin-induced cardiotoxicity and phytochemical-based cardioprotection: challenges and future strategies · Drug Metabolism Reviews · 2026
• Potential biomarkers and preventative interventions for muscle wasting in adolescent and young adults with cancer: A translational study · Scientific Reports · 2026
• Research Progress on Integrated Traditional Chinese and Western Medicine for the Prevention and Treatment of Anthracycline-Induced Cardiac Toxicity: A Multi-Target Regulatory Network and Clinical Translation Perspective · Journal of Contemporary Medical Practice · 2026
• Design, Synthesis, and Protective Activity against Doxorubicin-Induced Cardiotoxicity of Novel Water-Soluble Small-Molecule GPx Mimics · ACS Medicinal Chemistry Letters · 2026
• Sacubitril valsartan combined with bisoprolol reduces doxorubicin-induced cardiotoxicity in rats by attenuating oxidative stress · Experimental Biology and Medicine · 2026
• Onco-hypertension: hypertension induced by VEGF pathway inhibition · Frontiers in Cardiovascular Medicine · 2026
• Case Report: A case analysis of antitumor therapy and cardiovascular safety management in a breast cancer patient with multiple cardiovascular diseases · Frontiers in Cardiovascular Medicine · 2026
• Chemical Mechanisms and Predictive Analytics of Anthracycline-Induced Cardiotoxicity: A Data Science Approach · Zenodo (CERN European Organization for Nuclear Research) · 2026

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