Polyphenols and Flavonoids in microRNA-Regulated Pathways of Doxorubicin-Induced Cardiotoxicity: Mechanistic Evidence, Biomarker Potential and Translational Gaps

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.