Breast cancer remains one of the leading causes of cancer-related morbidity and mortality in women worldwide, and the clinical efficacy of doxorubicin (DOX) is frequently compromised by chemoresistance. Ferroptosis, an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation, has recently emerged as a critical determinant of tumor therapeutic response. At the same time, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been increasingly recognized as important regulators of gene expression, tumor progression, and drug sensitivity. This review summarizes current advances in understanding how ncRNAs modulate DOX resistance in breast cancer through ferroptosis-related pathways. We first outline the core mechanisms of ferroptosis, including dysregulated iron metabolism, lipid peroxide accumulation, and impaired antioxidant defenses, together with the major molecular bases of DOX resistance. We then highlight the distinct yet interconnected roles of miRNAs, lncRNAs, and circRNAs in regulating ferroptotic vulnerability. Emerging evidence indicates that aberrant ncRNA expression promotes a ferroptosis-resistant phenotype by strengthening the System Xc − –GSH–GPX4 antioxidant axis, activating the FSP1–CoQ10 pathway, and reprogramming iron homeostasis, thereby contributing to DOX resistance. Conversely, targeting specific ncRNAs can restore ferroptotic sensitivity and resensitize breast cancer cells to DOX. From a translational perspective, ncRNAs hold promise both as minimally invasive biomarkers for predicting therapeutic response and monitoring resistance, and as therapeutic targets for RNA-based or nanotechnology-enabled combination strategies. Nevertheless, major challenges remain, including compensatory ferroptosis networks, molecular subtype heterogeneity, limited delivery efficiency, and biosafety concerns. Overall, the ncRNA–ferroptosis axis represents a promising mechanistic framework and translational avenue for overcoming DOX resistance in breast cancer.
Yu et al. (Thu,) studied this question.