The CeRNA role of HOTAIR: sponging MiRs to promote chemoresistance.

Long non-coding RNA (lncRNA) HOTAIR has emerged as a pivotal, multimodal driver of therapeutic resistance across solid tumors. Beyond its canonical function as an epigenetic scaffold that recruits PRC2 and LSD1 to reprogram chromatin, HOTAIR also operates as a competing endogenous RNA (ceRNA) that sequesters tumor-suppressive microRNAs, thereby derepressing pro-survival and pro-invasive transcriptional programs. We synthesize evidence demonstrating that HOTAIR-centered ceRNA networks promote epithelial–mesenchymal transition (EMT), sustain protective autophagy, and elevate drug efflux capacity (ABCB1/ABCC1/ABCG2), converging on activation of PI3K/AKT/mTOR, STAT3, and Wnt/β-catenin signaling. Mechanistically, HOTAIR–miRNA–mRNA axes that meet canonical ceRNA validation criteria account for increased IC₅₀ values, apoptosis evasion, and sustained cancer stem–like states during cytotoxic and targeted therapies. Then we appraise therapeutic avenues to disrupt this network: (i) direct HOTAIR suppression with antisense oligonucleotides or siRNAs; (ii) durable transcriptional silencing via CRISPR interference; and (iii) restoration of miRNA function with mimics—or inhibition of reinforcing oncomiRs. Finally, we delineate key translational hurdles—including tumor-selective delivery, sequence/structure specificity, intra- and intertumoral heterogeneity, and compensatory ceRNA circuitry—and propose biomarker-driven, adaptive strategies that integrate HOTAIR expression, miRNA signatures, and functional readouts of EMT, autophagy, and efflux to enable patient stratification. Taken together, targeting the HOTAIR–miRNA axis offers a credible path to restoring drug sensitivity in refractory tumors and improving outcomes, contingent on precise patient selection, robust target engagement, and fit-for-purpose delivery technologies.