Targeting lncRNA-mediated networks to overcome doxorubicin resistance in cancer.

Doxorubicin (DOX) is widely used in the treatment of diverse cancers, but its efficacy is limited by the frequent emergence of drug resistance. Growing evidence demonstrates that long noncoding RNAs (lncRNAs) act as master regulators of DOX resistance, influencing survival signaling, apoptosis evasion, autophagy, epithelial-mesenchymal transition, and epigenetic remodeling. Despite their mechanistic diversity, lncRNAs converge on a limited set of actionable pathways, including PI3K/AKT/mTOR, anti-apoptotic regulators (BCL-2, MCL1), and autophagy-related networks. This review integrates cross-cancer evidence, highlighting ceRNA axes and signaling hubs, and explores therapeutic opportunities through direct lncRNA silencing, targeting of downstream effectors, and innovative delivery platforms such as lipid nanoparticles and engineered exosomes. We further propose a translational framework that emphasizes convergent resistance nodes, druggable pathways, and biomarker-driven patient stratification, outlining a roadmap from preclinical validation and CMC development to adaptive clinical trial design and companion diagnostic co-development. By uniting mechanistic insight with translational strategies, lncRNA-targeted interventions hold promise to overcome DOX resistance and advance precision oncology.