Non-coding RNA-mediated ferroptosis reprogramming in doxorubicin-resistant breast cancer: mechanistic evidence, subtype vulnerabilities, and translational strategies.

Abstract

Doxorubicin (DOX) resistance is a major factor limiting the efficacy of chemotherapy in breast cancer. Its development is associated not only with conventional mechanisms, such as enhanced drug efflux, increased DNA damage repair capacity, and evasion of apoptosis, but also with the adaptive escape of tumor cells from ferroptotic stress. Ferroptosis is a form of regulated cell death driven by the accumulation of iron-dependent lipid peroxidation and is coordinately regulated by multiple mechanisms, including the system Xc⁻-GSH-GPX4 axis, the FSP1-CoQ10 pathway, NRF2-mediated antioxidant responses, remodeling of iron metabolism, and regulation of lipid peroxidation. Non-coding RNA (ncRNAs), including miRNAs, lncRNAs, and circRNAs, can act on these ferroptosis defense modules through post-transcriptional regulation, competing endogenous RNA (ceRNA) networks, epigenetic modulation, and extracellular vesicle-mediated intercellular communication, thereby reshaping the sensitivity of breast cancer cells to DOX. This review systematically summarizes the major mechanisms by which ncRNAs regulate ferroptosis and contribute to DOX resistance in breast cancer, and further discusses subtype-specific differences in ncRNA-ferroptosis regulatory circuits among triple-negative, ER-positive, and HER2-positive breast cancers. In addition, this review highlights the potential value of circulating ncRNAs as resistance-associated biomarkers, as well as the translational prospects of miRNA mimics, siRNAs, antisense oligonucleotides (ASOs), and nanodelivery systems targeting the ncRNA-ferroptosis axis. Overall, ncRNA-mediated ferroptosis reprogramming provides a new mechanistic framework and potential therapeutic strategies for understanding and overcoming DOX resistance in breast cancer; however, its clinical application still requires further resolution of key challenges, including validation of causal evidence, insufficient delivery efficiency, off-target effects, and immunological safety.

Key Findings

• Non-coding RNAs (ncRNAs) regulate ferroptosis defense mechanisms such as the system Xc⁻-GSH-GPX4 axis, FSP1-CoQ10 pathway, and NRF2-mediated antioxidant responses in doxorubicin-resistant breast cancer.
• ncRNAs contribute to doxorubicin resistance by modulating ferroptosis sensitivity through post-transcriptional regulation, competing endogenous RNA networks, epigenetic modulation, and extracellular vesicle communication.
• Subtype-specific differences in ncRNA-ferroptosis regulatory circuits exist among triple-negative, ER-positive, and HER2-positive breast cancers, offering potential for targeted therapeutic strategies.

Clinical Significance

Citation

Yu Xiaojie, Xu An, Yao Longdiet al.. Non-coding RNA-mediated ferroptosis reprogramming in doxorubicin-resistant breast cancer: mechanistic evidence, subtype vulnerabilities, and translational strategies. World journal of surgical oncology. 2026-Jul-20.