Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and joint destruction. While genetic predisposition and environmental factors contribute to RA pathogenesis, the precise molecular mechanisms remain incompletely understood. Long non-coding RNAs (lncRNAs), a class of non-protein coding transcripts exceeding 200 nucleotides in length, are increasingly recognized as pivotal regulators of gene expression, playing significant roles in various biological processes and disease development. This abstract focuses on the emerging role of a specific lncRNA, Hox transcript antisense intergenic RNA (HOTAIR), in the context of RA.HOTAIR, initially identified as a regulator of HOX gene expression, has demonstrated pleiotropic effects in numerous cancers and other inflammatory diseases. Studies have implicated HOTAIR in the pathogenesis of RA through several mechanisms. Elevated HOTAIR expression has been consistently observed in synovial tissues and fibroblast-like synoviocytes (FLSs) from RA patients compared to healthy controls. This upregulation correlates with disease severity, suggesting a potential role in disease progression. Mechanistically, HOTAIR exerts its influence through epigenetic modifications, primarily by interacting with chromatin-modifying complexes such as PRC2 (Polycomb Repressive Complex 2) and LSD1 (Lysine-Specific Demethylase 1). These interactions lead to altered histone methylation patterns and gene silencing, impacting the expression of genes involved in inflammation, immune response, and cell proliferation. Specifically, HOTAIR has been shown to repress the expression of anti-inflammatory genes, while simultaneously upregulating pro-inflammatory cytokines, thereby contributing to the persistent inflammatory milieu characteristic of RA. Furthermore, HOTAIR's influence extends beyond epigenetic regulation. It can also modulate microRNA (miRNA) activity, impacting the expression of target genes involved in RA pathogenesis. The complex interplay between HOTAIR, miRNAs, and target genes forms a regulatory network contributing to the intricate pathophysiology of RA. Targeting HOTAIR, either through therapeutic silencing or through the modulation of its interacting partners, presents a promising avenue for the development of novel therapeutic strategies for RA. Further research is warranted to fully elucidate the precise mechanisms of HOTAIR action in RA and to explore its potential as a diagnostic biomarker and therapeutic target. This understanding could pave the way for personalized therapies tailored to specific RA patient subgroups exhibiting altered HOTAIR expression levels.