Polyphenols and Flavonoids in microRNA-Regulated Pathways of Doxorubicin-Induced Cardiotoxicity: Mechanistic Evidence, Biomarker Potential and Translational Gaps
- 1Department of Nutritional Science and Dietetics, Faculty of Health Sciences, University of Peloponnese, 24100 Kalamata, Greece
- 2Department of Medical Oncology, Athens Naval and Veterans Hospital, 11521 Athens, Greece
- 3Laboratory of Biology, Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Michalakopoulou 176, 11527 Athens, Greece
Abstract
Although doxorubicin remains a cornerstone of anticancer therapy, its clinical utility is limited by dose-dependent cardiotoxicity. Current tools for the early detection of doxorubicin-induced cardiotoxicity (DIC) remain suboptimal, prompting interest in microRNAs (miRNAs) as mechanistic regulators and circulating biomarkers. Natural cardioprotective compounds, particularly polyphenols and flavonoids, have also attracted attention because of their ability to modulate oxidative stress, mitochondrial dysfunction, inflammation, autophagy and regulated cell death. However, the mechanistic and translational strength of this evidence varies considerably. This critical narrative review is based on targeted PubMed literature searches up to 14 August 2026, supplemented by selective reference-list screening of relevant original articles and reviews. The literature search was not intended to be exhaustive, and the studies discussed were selected to illustrate different levels of mechanistic evidence. Studies investigating miRNA-mediated mechanisms in DIC were distinguished from circulating biomarker studies, while phytochemical evidence was classified as direct miRNA-linked, miRNA-associated without causal validation, or pathway-convergent. Among the selected examples, taxifolin provides direct miRNA-linked evidence involving the miR-200a/nuclear factor erythroid 2-related factor 2 (NRF2) pathway, with functional miR-200a inhibition demonstrated in H9c2 cells. Blueberry extract provided miRNA-associated evidence; miR-140-5p expression was assessed together with Sirt2 and Nrf2 expression, but a causal role for miR-140-5p was not functionally validated. For the other selected compounds, the available evidence was predominantly pathway-convergent. Although miRNAs and phytochemicals offer complementary perspectives on DIC mechanisms and cardioprotection, their clinical application remains premature. Future studies require functional miRNA validation, standardized biomarker assessment, pharmacokinetic evaluation and confirmation that cardioprotection does not compromise antitumor efficacy.
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BibTeX
@article{lampropoulou2026polyphenols,
title = {{Polyphenols and Flavonoids in microRNA-Regulated Pathways of Doxorubicin-Induced Cardiotoxicity: Mechanistic Evidence, Biomarker Potential and Translational Gaps}},
author = {Dimitra Ioanna Lampropoulou and Antigoni Kouskouti and Aristea Gioxari and Evangelia Pliakou and Konstantina Argyri and Vasileios Dedes and George Panoutsopoulos and Maria Gazouli},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209224},
url = {https://www.mdpi.com/1422-0067/27/20/9224},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Polyphenols and Flavonoids in microRNA-Regulated Pathways of Doxorubicin-Induced Cardiotoxicity: Mechanistic Evidence, Biomarker Potential and Translational Gaps
AU - Dimitra Ioanna Lampropoulou
AU - Antigoni Kouskouti
AU - Aristea Gioxari
AU - Evangelia Pliakou
AU - Konstantina Argyri
AU - Vasileios Dedes
AU - George Panoutsopoulos
AU - Maria Gazouli
PY - 2026
DA - 2026/10/17
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209224
UR - https://www.mdpi.com/1422-0067/27/20/9224
AB - Although doxorubicin remains a cornerstone of anticancer therapy, its clinical utility is limited by dose-dependent cardiotoxicity. Current tools for the early detection of doxorubicin-induced cardiotoxicity (DIC) remain suboptimal, prompting interest in microRNAs (miRNAs) as mechanistic regulators and circulating biomarkers. Natural cardioprotective compounds, particularly polyphenols and flavonoids, have also attracted attention because of their ability to modulate oxidative stress, mitochondrial dysfunction, inflammation, autophagy and regulated cell death. However, the mechanistic and translational strength of this evidence varies considerably. This critical narrative review is based on targeted PubMed literature searches up to 14 August 2026, supplemented by selective reference-list screening of relevant original articles and reviews. The literature search was not intended to be exhaustive, and the studies discussed were selected to illustrate different levels of mechanistic evidence. Studies investigating miRNA-mediated mechanisms in DIC were distinguished from circulating biomarker studies, while phytochemical evidence was classified as direct miRNA-linked, miRNA-associated without causal validation, or pathway-convergent. Among the selected examples, taxifolin provides direct miRNA-linked evidence involving the miR-200a/nuclear factor erythroid 2-related factor 2 (NRF2) pathway, with functional miR-200a inhibition demonstrated in H9c2 cells. Blueberry extract provided miRNA-associated evidence; miR-140-5p expression was assessed together with Sirt2 and Nrf2 expression, but a causal role for miR-140-5p was not functionally validated. For the other selected compounds, the available evidence was predominantly pathway-convergent. Although miRNAs and phytochemicals offer complementary perspectives on DIC mechanisms and cardioprotection, their clinical application remains premature. Future studies require functional miRNA validation, standardized biomarker assessment, pharmacokinetic evaluation and confirmation that cardioprotection does not compromise antitumor efficacy.
SN - 1422-0067
ER -