HOTAIR in cancer: a context-dependent regulatory platform linking molecular mechanisms, tumor progression, and clinical translation.

Long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR) has emerged as a representative cancer-associated lncRNA with diverse regulatory functions in tumor biology. Initially characterized as an epigenetic scaffold that recruits polycomb repressive complex 2 (PRC2) and lysine-specific demethylase 1 (LSD1), HOTAIR is now recognized as a multifunctional regulatory platform involved in chromatin remodeling, RNA-mediated regulation, metabolic adaptation, cellular plasticity, and therapeutic resistance. Increasing evidence indicates that the biological effects of HOTAIR are highly context dependent and are influenced by tumor lineage, molecular partners, RNA modifications, and cellular environments, challenging the concept of HOTAIR as a universally oncogenic factor. In this review, we summarize recent advances in understanding the molecular architecture and regulatory mechanisms of HOTAIR, including its interactions with chromatin-modifying complexes, RNA-binding proteins, and post-transcriptional regulatory networks. We further discuss the involvement of HOTAIR in cancer progression, emphasizing its roles in tumor adaptation, metastasis, epithelial-mesenchymal transition, metabolic regulation, and resistance to anticancer therapies. We also summarize current approaches for HOTAIR detection and discuss their potential clinical relevance and limitations. Although HOTAIR represents a promising candidate for biomarker development and therapeutic intervention, several challenges remain before clinical translation, including tumor heterogeneity, insufficient clinical validation, delivery limitations of HOTAIR-targeting agents, potential off-target effects, and the need for precise patient selection. Future studies integrating molecular profiling, functional characterization, and clinical evaluation will be essential to determine the translational value of HOTAIR-based strategies. A deeper understanding of HOTAIR as a context-dependent regulatory hub may facilitate the development of more precise approaches for cancer diagnosis and therapy.