Introduction

Long non-coding RNAs (lncRNAs) are a class of RNA molecules longer than 200 nucleotides that do not encode proteins, and they have attracted extensive attention in the fields of gene regulation and tumor biology in recent years. lncRNAs not only play key roles in normal cellular differentiation, development, replication and environmental adaptation but are also involved in the initiation, progression and metastasis of various tumors.1 Among them, HOTAIR (HOX transcript antisense intergenic RNA) is one of the most intensively studied lncRNAs. Abnormally high expression of HOTAIR has been demonstrated in many cancers and is closely associated with proliferation, invasion, metastasis and drug resistance of tumor cells.2 Despite extensive research, several critical mechanistic questions remain unresolved. First, how HOTAIR achieves target gene specificity is still largely unknown; current evidence suggests possible involvement of RNA-RNA interactions at the 3′ end of target genes, m6A modification-mediated recruitment of SNAIL/EZH2 complexes, or localization to open chromatin regions, but the precise determinants of selectivity remain elusive.3,4 Second, HOTAIR functions are highly context-dependent, exhibiting opposing roles depending on cell type, subcellular localization, and microenvironment. For example, in bone biology, HOTAIR inhibits osteogenic differentiation in bone marrow stromal cells (nuclear localization) but promotes osteoblast function in mature osteoblasts (cytoplasmic localization).5 Such context-dependent functions have also been observed in cancer.6,7 Third, the prognostic value of HOTAIR varies across studies, largely due to tumor heterogeneity (differences in patient clinical characteristics and tumor biological/genetic features) as well as methodological heterogeneity in detection strategies (eg, tissue RNA levels versus serum exosomal HOTAIR, subcellular localization).8,9 These inconsistencies highlight the need for standardized detection methods and stratified analyses.

HOTAIR regulates the biological behavior of tumor cells through multiple molecular mechanisms. It can act as a “molecular sponge” to sequester specific miRNAs and thereby release their inhibition of target genes, or recruit chromatin-modifying complexes such as Polycomb repressive complex 2 (PRC2) and histone demethylase complexes (eg LSD1/NuRD) to modulate the epigenetic state of target genes and affect gene transcription.2,10 Through these mechanisms, HOTAIR has become a key node in epigenetic regulation in cancer, modulating tumor cell proliferation, migration, invasion and the maintenance of cancer stem cell properties.11,12

Clinical studies have shown that HOTAIR is highly expressed in a wide range of tumor types, including breast cancer, lung cancer, hepatocellular carcinoma, gastric cancer, colorectal cancer, thyroid cancer and bladder cancer, and its expression level is closely associated with tumor malignancy, metastatic potential and patient prognosis.13–18 For example, in breast cancer, HOTAIR promotes cancer stem cell self-renewal and tumor expansion by activating the NF-κB pathway and thereby drives tumor progression.19 In lung cancer, HOTAIR participates in epigenetic regulation, promotes epithelial–mesenchymal transition (EMT) and contributes to resistance to EGFR-TKIs.20,21 In papillary thyroid carcinoma, high HOTAIR expression correlates negatively with tumor size, depth of invasion, lymph node metastasis and patient survival.14,22

In addition, the role of HOTAIR in the tumor microenvironment has gradually been revealed. Tumor-derived exosomes carrying HOTAIR can induce tumor-associated immune cells, such as macrophages, to polarize toward the pro-tumorigenic M2 phenotype, thereby promoting immune escape and metastasis.19,23,24 HOTAIR also participates in tumor angiogenesis by modulating signaling pathways such as Hedgehog and PI3K/AKT, promoting tumor cell invasion and metastasis.25,26

At the molecular level, HOTAIR not only directly regulates chromatin structure and gene expression but also forms competing endogenous RNA (ceRNA) networks with multiple miRNAs, regulating numerous signaling pathways, such as miR-214-3p/FLOT1, miR-20b-5p/RRM2/PI3K/AKT and miR-130a-3p/Suv39H1.27–29 These complex regulatory networks enable HOTAIR to exert diverse functions during tumorigenesis and tumor progression.

In summary, lncRNA HOTAIR has become a research hotspot in the study of tumor molecular mechanisms. It is aberrantly overexpressed in various tumor types and, by regulating chromatin remodeling, gene expression, interactions with other non-coding RNAs and signal transduction pathways, it influences tumor cell proliferation, migration, invasion, angiogenesis and drug resistance.17,30 The multifaceted mechanisms of HOTAIR in tumorigenesis and its complex interactions with the tumor immune microenvironment provide potential molecular targets and biomarkers for cancer diagnosis, prognostic assessment and therapy.31 These features highlight the broad clinical application prospects of HOTAIR. Therefore, systematically summarizing the molecular mechanisms of HOTAIR in cancer is of great significance for deepening our understanding of tumor biology and developing novel therapeutic strategies. These features highlight the broad clinical application prospects of HOTAIR. A schematic diagram summarizing the multi-layered molecular mechanisms of HOTAIR in cancer is presented in Figure 1. Therefore, systematically summarizing the molecular mechanisms of HOTAIR in cancer is of great significance for deepening our understanding of tumor biology and developing novel therapeutic strategies. Addressing these knowledge gaps is essential for understanding HOTAIR’s precise roles in tumor biology and for translating this knowledge into clinical practice, which is the primary goal of this review.

Figure 1 Schematic diagram illustrating the multi-layered molecular mechanisms of lncRNA HOTAIR in cancer, including epigenetic regulation (PRC2/LSD1), miRNA sponging, and activation of downstream signaling pathways (Wnt/β-catenin, PI3K/AKT/mTOR, NF-κB).

Structural Features of HOTAIR and Regulatory Mechanisms of Its ExpressionGene Structure and Transcriptional Characteristics of HOTAIR

HOTAIR (HOX transcript antisense intergenic RNA) is located on human chromosome 12q13.13 and has a length of approximately 2158 nucleotides. As a long non-coding RNA, HOTAIR possesses a complex gene structure with multiple functional domains that enable it to interact with diverse protein complexes and exert important regulatory functions. Studies have shown that the HOTAIR gene sequence contains conserved non-coding elements that likely originated in vertebrate ancestors and have been dispersed to different loci through genomic duplication. Notably, a 32-nucleotide conserved non-coding element (CNE) has been identified as an ancient sequence of HOTAIR. This CNE is present not only in HOTAIR but is also embedded in a non-coding transcript of HOXD11. These two transcripts can form a regulatory network via sequence complementarity, exhibiting dual cis- and trans-regulatory functions. The evolutionary conservation of this CNE suggests that HOTAIR’s regulatory functions are deeply rooted in vertebrate biology, and its hijacking in cancer may reflect the co-option of an ancient stress-response or developmental mechanism. Specifically, transcription of HOTAIR can regulate the expression of the neighboring HOXC11 gene at its own locus (cis-regulation), while its sequence complementarity with HOXD11 may mediate regulatory effects across distinct genomic loci (trans-regulation).32

In addition, HOTAIR transcription is regulated by multiple transcription factors and epigenetic modifications, and displays strong tissue specificity and tumor-specific expression patterns. For example, HOTAIR is significantly upregulated in hepatocellular carcinoma, breast cancer, ovarian cancer and several other malignancies, and changes in its transcript level are closely associated with tumor malignancy.33,34 Through its functional domains, HOTAIR can bind to several protein complexes, including Polycomb repressive complex 2 (PRC2) and lysine-specific demethylase 1 (LSD1), thereby mediating chromatin remodeling and epigenetic regulation of gene expression and influencing tumor cell proliferation, migration, invasion and other biological processes.35,36 Thus, the gene structure and transcriptional characteristics of HOTAIR provide a molecular basis for its multifunctional regulatory roles and make it an important target in cancer research.

Regulatory Mechanisms Governing HOTAIR Expression

HOTAIR expression is controlled at multiple levels through a complex network involving DNA methylation, histone modifications and transcription factors. At the DNA methylation level, HOTAIR can regulate the expression of DNA methyltransferase 1 (DNMT1) and thereby indirectly affect the methylation status of target genes. For example, in gastric adenocarcinoma, HOTAIR promotes tumor progression by regulating DNMT1 to induce hypermethylation and silencing of the tumor suppressor gene PCDH10.37 In terms of histone modifications, HOTAIR recruits the PRC2 complex and guides trimethylation of histone H3 lysine 27 (H3K27me3), leading to transcriptional repression of target genes. HOTAIR expression is also influenced by H3K4 trimethylation (H3K4me3), a mark generally associated with transcriptional activation. For instance, in neuroblastoma cells treated with lauric acid, HOTAIR modulates H3K4me3 to promote expression of the glucose transporter GLUT1, illustrating its epigenetic regulatory role in metabolic reprogramming.38

With respect to transcription factors, key regulators such as c-Myc and E2F1 participate in the transcriptional control of HOTAIR. In acute myeloid leukemia (AML), the transcription factor C/EBPβ can upregulate HOTAIR expression and promote cell differentiation.39 Moreover, inflammatory factors and signaling molecules in the tumor microenvironment can also modulate HOTAIR expression and contribute to its aberrant activation in cancer. For example, activation of the inflammation-related NF-κB signaling pathway can upregulate HOTAIR, thereby regulating downstream gene expression and promoting tumor cell proliferation and survival.38 In tumor cells, the transcription factor YY1 is regulated by HOTAIR, which can act as a “sponge” for miR-1 and miR-206 to modulate YY1 expression and promote tumor cell proliferation and migration.40 Taken together, HOTAIR expression is governed by multidimensional and multilayered regulatory mechanisms involving epigenetic modifications, transcription factor networks and tumor microenvironmental signals, which collectively drive its aberrant expression during tumorigenesis and tumor progression.

Aberrant HOTAIR Expression and Its Association with Cancer Prognosis

Multiple clinical studies have demonstrated that HOTAIR is abnormally overexpressed in a wide spectrum of cancers and that its expression level is closely correlated with tumor malignancy, metastatic potential and patient prognosis. In breast cancer, hepatocellular carcinoma, ovarian cancer, non-small cell lung cancer and colorectal cancer, high HOTAIR expression is significantly associated with increased invasiveness, higher risk of metastasis and poorer overall survival.41,42 For example, in non-small cell lung cancer, increased HOTAIR expression is associated with advanced stage and negatively correlated with miR-221 levels. HOTAIR promotes tumor cell proliferation and suppresses apoptosis by negatively regulating miR-221, thereby affecting patient prognosis.43 In ovarian cancer, HOTAIR enhances resistance to chemotherapeutic agents such as paclitaxel, and silencing HOTAIR expression can increase drug sensitivity and improve treatment efficacy.34

HOTAIR influences prognosis through multiple molecular mechanisms. It can competitively bind miRNAs such as miR-206, miR-214-3p and miR-148b, regulating expression of key target genes and thereby promoting tumor cell proliferation, migration and invasion.37,40 Clinical data indicate that high HOTAIR expression often predicts unfavorable survival outcomes and higher risk of recurrence, supporting its role as an important biomarker for prognostic evaluation and a potential therapeutic target in cancer.33 Overall, aberrant HOTAIR expression is tightly linked to tumorigenesis, cancer progression and patient outcome, highlighting its critical role and clinical significance in tumor biology.

Epigenetic Regulatory Mechanisms Mediated by HOTAIRInteraction Between HOTAIR and the PRC2 Complex

As an important long non-coding RNA, HOTAIR exerts epigenetic regulatory effects through the specific binding of its 5′ domain to the PRC2, thereby mediating trimethylation of histone H3 lysine 27 (H3K27me3) and silencing tumor suppressor genes. The catalytic core component of PRC2, enhancer of zeste homolog 2 (EZH2), is a histone methyltransferase that catalyzes H3K27 trimethylation, leading to the formation of repressive chromatin and subsequent transcriptional silencing. In multiple tumor types, HOTAIR recruits PRC2 to target gene promoter regions, promotes H3K27me3 modification at these loci, and downregulates tumor suppressor genes, thereby facilitating tumor cell proliferation and invasion. For example, in liver cancer, HOTAIR binds to EZH2 in PRC2 and silences miR-145-5p, thereby regulating NUAK1 expression and promoting EMT and metastasis.44 In breast cancer, HOTAIR expression is closely associated with tumor grade and prognosis, and it regulates the expression of numerous genes involved in tumor progression via PRC2-mediated H3K27me3.21,33 In non-small cell lung cancer, HOTAIR enhances EZH2-mediated H3K27me3 to silence cell-cycle inhibitors such as p16 and p21, promoting cell-cycle progression and the development of drug resistance.21

Small-molecule compounds such as AC1Q3QWB (AQB) can selectively disrupt the interaction between HOTAIR and EZH2, block PRC2 recruitment, and restore tumor suppressor gene expression, showing promising therapeutic potential.45 In addition, vitamin D has been hypothesized to bind specific structural domains of HOTAIR and thereby inhibit the interaction between HOTAIR and PRC2, exerting antitumor effects.46 Collectively, the binding of HOTAIR to PRC2 is a core mechanism underlying its epigenetic regulatory functions. By promoting H3K27 trimethylation and silencing tumor suppressor genes, HOTAIR drives malignant progression of tumor cells.

Synergistic Action of HOTAIR and the LSD1 Complex

The 3′ domain of HOTAIR can bind the histone demethylase LSD1 (lysine-specific demethylase 1), regulating the demethylation of histone H3 lysine 4 (H3K4) and further modulating gene expression. LSD1 removes mono- and dimethyl groups from H3K4, marks typically associated with active promoters, and thus its demethylase activity is generally linked to transcriptional repression. Through simultaneous binding to PRC2 and LSD1 complexes, HOTAIR forms a multifunctional epigenetic regulatory scaffold that enables combinatorial control of target genes.

In glioblastoma, the combined use of an inhibitor targeting the HOTAIR–EZH2 interaction (AQB) and an LSD1 inhibitor can significantly modulate the expression of cell-cycle-related genes and promote tumor cell apoptosis, exhibiting synergistic antitumor effects.35 In breast cancer, the interaction between HOTAIR and LSD1 plays a critical role in EMT, and the LSD1-binding domain of HOTAIR is indispensable for promoting cell migration.47 Moreover, LSD1 displays a non-canonical scaffold function associated with HOTAIR in systemic sclerosis, regulating the expression of fibrosis-related genes.48 Although the catalytic activity of LSD1 is important for certain pathological processes, its binding to HOTAIR mainly contributes to the assembly of regulatory complexes, adding further complexity to gene control. The synergy between HOTAIR and LSD1 not only reinforces gene silencing at the epigenetic level but also enriches the repertoire of HOTAIR-mediated molecular mechanisms, offering multiple potential strategies for targeted therapy.

HOTAIR-Mediated Chromatin Remodeling and Gene Expression Regulation

HOTAIR regulates chromatin structure and affects transcription of cancer-related genes by recruiting various epigenetic regulators. In addition to interacting with PRC2 and LSD1, HOTAIR can bind to subunits of chromatin remodeling complexes such as SMARCB1 and ARID1A of the SWI/SNF complex,49 thereby mediating dynamic changes in chromatin architecture and modulating gene expression. Genome-wide studies have demonstrated that HOTAIR plays an important role in regulating chromatin accessibility and histone modifications at promoters and enhancers.4

Furthermore, HOTAIR can engage in multivalent interactions with RNA-binding proteins, which remodel its own structure and facilitate binding to target RNAs, thereby enhancing PRC2 catalytic activity.50 HOTAIR-mediated epigenetic regulation involves not only gene silencing but also gene activation and dynamic control. For example, in neurons, HOTAIR modulates histone modifications at the BDNF promoter and participates in dynamic regulation of gene expression.51 In tumor cells, HOTAIR-mediated chromatin remodeling underpins phenotypic transitions and malignant progression, promoting cell proliferation, migration and invasion.52,53

HOTAIR-driven changes in chromatin structure also influence immune evasion mechanisms. In glioma, HOTAIR activates NF-κB signaling to upregulate PD-L1 expression, enabling tumor cells to evade immune surveillance.7 Overall, HOTAIR-mediated chromatin remodeling encompasses not only histone modifications but also broad chromatin-level regulatory mechanisms that shape the transcriptional landscape and support malignant phenotypes of tumor cells.

In summary, as a key epigenetic regulator, HOTAIR coordinates multiple mechanisms through its 5′ domain binding PRC2 to mediate H3K27 trimethylation, its 3′ domain binding LSD1 to modulate H3K4 demethylation, and its ability to orchestrate chromatin remodeling. Together, these processes form a complex regulatory network that silences tumor suppressor genes and regulates oncogene expression, thereby promoting tumor cell proliferation, migration, invasion and immune escape and providing a molecular basis for cancer development as well as potential therapeutic targets.

An Integrative Model of HOTAIR’s Multilayered Mechanisms

Based on the evidence summarized above, we propose a hierarchical framework for understanding HOTAIR’s molecular functions. At the core lies the canonical PRC2-recruitment mechanism, which has been validated across multiple cancer types (glioma,7 ovarian cancer,54 endometrial cancer)55 and is widely considered the most fundamental HOTAIR-dependent epigenetic pathway.56 This core mechanism is often amplified or supplemented by context-dependent regulations. For example, in cervical cancer, HOTAIR simultaneously activates both PI3K/AKT and Wnt/β-catenin via the HIF1α/PTEN axis,57 and also acts as a ceRNA by sponging miR-214-3p to further enhance Wnt signaling.58 In breast cancer, HOTAIR regulates the Wnt/β-catenin pathway59 and its function is modulated by m6A epitranscriptomic modification at the A783 residue.60 In glioma, NF-κB activation predominates, alongside LSD1 co-recruitment.61 Emerging mechanisms such as exosome-mediated communication require further validation across additional cancer types. Notably, no single mechanism operates in isolation; the relative contribution of each layer likely depends on the tumor’s epigenetic landscape and microenvironment. Discrepancies across studies should therefore be interpreted not as contradictions but as reflections of this context-dependent complexity. This integrative model provides a conceptual framework for designing future mechanistic studies and for developing cancer type-specific therapeutic strategies targeting HOTAIR.

Regulatory Roles of HOTAIR in Cancer-Related Signaling PathwaysHOTAIR Regulation of the Wnt/β-Catenin Signaling Pathway

HOTAIR exerts oncogenic effects in multiple tumors by modulating the Wnt/β-catenin signaling pathway. Wnt/β-catenin signaling is a key regulator of cell proliferation, migration and differentiation, and its aberrant activation is closely related to the development of many cancers. Studies have shown that HOTAIR promotes tumor cell proliferation and migration by regulating the expression of key components of the Wnt pathway.

In cervical cancer HeLa cells, HOTAIR knockdown significantly reduces Wnt/β-catenin pathway activity while upregulating negative regulators such as PCDH10, SOX17, AJAP1 and MAGI2. The decreased promoter methylation of these genes suggests that HOTAIR promotes overactivation of Wnt signaling by epigenetically silencing negative regulators.62 In pancreatic cancer models, high HOTAIR expression increases the expression of Wnt/β-catenin-related genes (β-catenin, cyclin D1, c-Myc, LEF-1, c-Jun) and promotes EMT, enhancing tumor cell proliferation, migration and invasion, whereas HOTAIR silencing effectively suppresses these processes.63 In thyroid cancer and breast cancer, HOTAIR has also been shown to promote tumor progression by modulating Wnt/β-catenin signaling, and its expression level is closely associated with tumor invasion and metastasis.64,65

Mechanistically, HOTAIR can also function as a ceRNA by sponging miRNAs such as miR-214-3p and miR-34a, indirectly regulating the expression of Wnt pathway target genes and further activating the pathway.27,65 Overall, HOTAIR enhances Wnt/β-catenin signaling activity through multi-level regulation of key pathway components, thereby promoting malignant behavior of tumor cells and representing a potential therapeutic target.66

Crosstalk Between HOTAIR and the PI3K/Akt/mTOR Signaling Pathway

The PI3K/Akt/mTOR pathway plays a central role in regulating cell survival, proliferation and metabolism, and its aberrant activation is a major driver of tumor progression and therapy resistance. Increasing evidence indicates that HOTAIR activates the PI3K/Akt/mTOR pathway, thereby enhancing tumor cell survival and drug resistance.

In breast cancer cells, silencing HOTAIR markedly reduces the expression and phosphorylation of PI3K, Akt and mTOR, inhibits cell proliferation and promotes apoptosis, suggesting that HOTAIR promotes tumor growth by positively regulating this pathway.67,68 In colorectal cancer, the HOTAIR/miR-326/FUT6 axis modulates α1,3-fucosylation of CD44, which in turn activates the PI3K/Akt/mTOR pathway and promotes tumor progression and liver metastasis.69

Moreover, HOTAIR forms a regulatory axis with hypoxia-inducible factor 1α (HIF-1α), upregulating DNMT1-mediated promoter hypermethylation of PTEN, thereby suppressing PTEN expression and driving persistent activation of both PI3K/Akt and Wnt/β-catenin pathways in cervical cancer.46 In prostate cancer, aberrant HOTAIR expression is associated with PI3K/Akt/mTOR pathway activation, and natural products such as curcumin can exert anticancer effects by downregulating HOTAIR and inhibiting this pathway.70

HOTAIR also contributes to chemoresistance via PI3K/Akt/mTOR activation. For example, in breast cancer, HOTAIR-induced activation of the PI3K/Akt/mTOR pathway is implicated in doxorubicin resistance, and HOTAIR knockdown can reverse this resistance.68 Collectively, HOTAIR activates PI3K/Akt/mTOR signaling through diverse mechanisms to promote tumor cell survival, proliferation and drug resistance, making it an important molecular target in cancer therapy.

HOTAIR Regulation of the NF-κB Pathway and the Formation of an Inflammatory Tumor Microenvironment

The inflammatory tumor microenvironment is an indispensable component of tumorigenesis and progression. The NF-κB signaling pathway is a central regulator of inflammatory responses; its activation promotes the expression of proinflammatory factors and shapes a microenvironment conducive to tumor growth. Studies have shown that HOTAIR contributes to the construction of a protumor inflammatory microenvironment in multiple cancers by activating NF-κB signaling.

In breast cancer, for example, HOTAIR recruits PRC2 to repress IκBα expression, thereby relieving inhibition of NF-κB signaling and activating the NF-κB pathway. This leads to upregulation of c-Myc and cyclin D1, promoting self-renewal of breast cancer stem cells and tumor expansion.19 This mechanism not only enhances tumor cell proliferation and migration but also regulates immune cells in the tumor microenvironment to intensify inflammatory responses, creating a positive feedback loop that further augments HOTAIR expression and function.

Similarly, in osteoarthritis and other inflammatory diseases, HOTAIR regulates NF-κB and related pathways to promote the production of inflammatory mediators and aggravate disease progression.71 HOTAIR also interacts with multiple miRNAs and transcription factors to modulate NF-κB activity, thereby driving malignant progression and chemoresistance. In turn, the inflammatory microenvironment can upregulate HOTAIR expression through various mechanisms, forming a positive feedback network that facilitates tumor evolution.

In summary, HOTAIR promotes the expression of proinflammatory factors and formation of an inflammatory tumor microenvironment by activating NF-κB signaling, thereby contributing to tumor initiation, progression and drug resistance and serving as an important regulator of the tumor immune microenvironment (Table 1).

Table 1 Dominant and Context-Dependent Mechanisms of HOTAIR in Major Cancer Types

Conclusions

It is important to note that the vast majority of cancer studies report a pro-oncogenic role for HOTAIR and an association with high expression and poor prognosis. To date, no study has demonstrated a favorable prognostic value of HOTAIR in malignancies. However, a more balanced view requires consideration of several points. First, in non-cancer tissues such as bone and adipose tissue, HOTAIR exhibits clear context-dependent bidirectional functions. For example, HOTAIR inhibits osteogenic differentiation in bone marrow stromal cells (nuclear localization) but promotes osteoblast function in mature osteoblasts (cytoplasmic localization).46 Similarly, in adipocytes, HOTAIR expression correlates inversely with regional fat mass and suppresses adipocyte differentiation.72 Second, the function of HOTAIR is not intrinsically fixed; epitranscriptomic modifications such as m6A methylation at the A783 residue can switch HOTAIR from a pro-oncogenic to an anti-oncogenic transcriptional program.73 These findings suggest that HOTAIR’s activity is highly context-dependent and can be modulated by post-transcriptional modifications. Third, methodological heterogeneity across studies—including differences in detection strategies (tissue RNA vs serum exosomal HOTAIR), normalization controls, and lack of standardized cut-off values—may contribute to variability in reported results. Addressing these issues will be critical for future clinical translation.

In summary, the core mechanisms through which HOTAIR drives cancer progression are now well-defined: (i) recruitment of PRC2 to mediate H3K27me3 and silence tumor suppressors; (ii) co-recruitment of LSD1 for H3K4 demethylation; (iii) acting as a ceRNA to sponge multiple miRNAs (eg, miR-214-3p, miR-34a, miR-20b-5p); and (iv) cross-activating the Wnt/β-catenin, PI3K/AKT/mTOR, and NF-κB signaling pathways. While the vast majority of cancer studies report a consistent pro-oncogenic role, the context-dependent bidirectional functions observed in non-cancer tissues (eg, bone, adipose) and the reversible effects mediated by m6A modification (eg, at A783) caution against viewing HOTAIR as a monolithic oncogene.

For future translation, we propose three concrete directions. First, structure-based inhibitors that disrupt the HOTAIR-PRC2 interaction (eg, AC1Q3QWB derivatives) should be optimized and tested in preclinical models. Second, prospective cohort studies using standardized protocols (eg, qPCR with uniform normalization controls) are needed to validate HOTAIR in liquid biopsies (serum, urine exosomes) as a non-invasive biomarker, including assessment of sensitivity, specificity, and cut-off values. Third, integrating multi-omics data (transcriptomic, epigenomic, and clinical) with artificial intelligence models may help resolve functional heterogeneity across tumor types and guide personalized HOTAIR-targeted strategies. Addressing these priorities will accelerate the clinical translation of HOTAIR-based diagnostics and therapeutics.

Abbreviations

lncRNA, The long non-coding RNA; HOTAIR, HOX transcript antisense RNA; miRNAs, microRNAs; PRC2, Polycomb repressive complex 2; EMT, epithelial–mesenchymal transition; ceRNA, competing endogenous RNA; CNE, conserved non-coding element; PRC2, Polycomb repressive complex 2; LSD1, lysine-specific demethylase 1; DNMT1, DNA methyltransferase 1; H3K27me3, histone H3 lysine 27; H3K4me3, H3K4 trimethylation; AML, acute myeloid leukemia; PRC2, Polycomb repressive complex 2; EZH2, zeste homolog 2; AQB, AC1Q3QWB; H3K4, histone H3 lysine 4; HIF-1α, hypoxia-inducible factor 1α.

Ethical Considerations

This study did not involve direct contact with human participants or the collection of personal health information. Therefore, no ethical approval or informed consent was required.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the Basic research project (natural science) of Department of Guizhou Science and Technology, zk [2023], general-210, National Natural Science Foundation (8236110133).

Disclosure

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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