LincRNA-Cox2 at the crossroads of innate immunity and inflammation: mechanisms, disease associations, and therapeutic perspectives.

Long intergenic non-coding RNA associated with cyclooxygenase-2 (LincRNA-Cox2) has emerged as a prototypical immune-regulatory long non-coding RNA (lncRNA) that integrates pattern-recognition receptor signaling with chromatin remodeling and effector gene transcription in innate immune cells. Originally identified as a highly inducible transcript adjacent to the Ptgs2/Cox2 locus in macrophages, lincRNA-Cox2 displays expression restricted by stimulus and cell type, nuclear localization, and isoform diversity. Mechanistic studies demonstrate that lincRNA-Cox2 exerts both repressive and activating effects on immune-response genes by assembling with heterogeneous nuclear ribonucleoproteins, SWI/SNF complexes, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and other signaling intermediates, thereby tuning inflammasome activation, autophagy, Janus kinase/signal transducers and activators of transcription (JAK–STAT) signaling, and cytokine production. Beyond macrophages, lincRNA-Cox2 modulates inflammatory pathways in microglia, dendritic cells, epithelial cells, smooth muscle cells, and other structural cell types, positioning it as a shared regulatory node across tissues. Consistent with these mechanistic roles, altered lincRNA-Cox2 expression has been linked to acute lung injury, chronic smoke-induced airway inflammation, sepsis, bacterial and mycobacterial infections, neuroinflammation, osteoarthritis, metabolic kidney injury, atherosclerosis, pulmonary arterial hypertension, and inflammatory bowel disease. In several of these settings, experimental silencing or pharmacological modulation of lincRNA-Cox2-centered axes ameliorates tissue damage, while clinical studies highlight its potential as a circulating or tissue biomarker. This review synthesizes current knowledge on the biogenesis and molecular actions of lincRNA-Cox2, collates evidence for its involvement in inflammatory, infectious, and malignant disease contexts, and discusses emerging therapeutic and translational opportunities. Together, available data support lincRNA-Cox2 as a context-dependent regulator at the crossroads of innate immunity and inflammation, and as a promising yet complex target for diagnostic and RNA-based therapeutic strategies in human disease.