Targeting MicroRNAs in doxorubicin-induced cardiotoxicity: A systematic review of transfection studies

Doxorubicin-induced cardiotoxicity (DIC) remains a major limitation of anthracycline-based chemotherapy, characterized by progressive myocardial dysfunction and heart failure. Increasing evidence implicates microRNAs (miRNAs) as critical post-transcriptional regulators of cardiomyocyte survival; however, their pharmacological relevance is often inferred from expression profiling rather than functional validation. This systematic review synthesizes evidence from preclinical studies (2015-2025) employing transfection-based approaches, including miRNA mimics and inhibitors, with downstream validation by qRT-PCR, Western blotting, and luciferase assays. A total of 24 studies were included, identifying key miRNAs that modulate DIC through distinct yet convergent molecular pathways. Protective miRNAs such as miR-200a, miR-21, and miR-29b attenuated oxidative stress and apoptosis primarily via activation of the Keap1/Nrf2 axis and suppression of Bax-dependent mitochondrial pathways. In contrast, miR-140-5p, miR-128-3p, and miR-34a-5p exacerbated cardiotoxicity by inhibiting antioxidant signaling, disrupting PPAR-γ and Sirt3 pathways, and promoting ferroptotic and pyroptotic cell death. Emerging evidence also implicates miRNA-mediated regulation of endoplasmic reticulum stress and autophagy, although inflammatory and fibrotic signaling pathways remain underexplored. Collectively, these findings position miRNAs as mechanistically relevant modulators of doxorubicin cardiotoxicity and potential pharmacological targets. However, the predominance of non-human models, limited pathway integration, and lack of clinically translatable delivery strategies constrain therapeutic advancement. Future studies should prioritize human-relevant systems, multi-omics integration, and targeted delivery platforms to enable the translation of miRNA-based interventions into cardioprotective therapies.