Targeting lncRNA-mediated networks to overcome doxorubicin resistance in cancer

Feb 14, 2026Critical reviews in oncology/hematology

Targeting Long Noncoding RNA Networks to Overcome Cancer Resistance to Doxorubicin

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Abstract

Long noncoding RNAs (lncRNAs) may significantly influence doxorubicin (DOX) resistance across various cancers.

lncRNAs are linked to mechanisms of drug resistance, including survival signaling and apoptosis evasion.
These molecules affect key pathways such as PI3K/AKT/mTOR and anti-apoptotic factors like BCL-2 and MCL1.
Therapeutic strategies may involve silencing lncRNAs and targeting downstream effectors to combat resistance.
Innovative delivery methods, such as lipid nanoparticles and engineered exosomes, could enhance treatment efficacy.
A proposed translational framework aims to integrate resistance mechanisms with patient-specific strategies for better outcomes.

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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.

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Targeting lncRNA-mediated networks to overcome doxorubicin resistance in cancer

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