Non-coding RNAs (ncRNAs) have emerged as critical regulators of osteoarthritis (OA) pathogenesis by modulating gene expression at the epigenetic, transcriptional, and post-transcriptional levels. Among the major ncRNA classes, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) regulate key biological processes involved in OA progression, including extracellular matrix degradation, synovial inflammation, chondrocyte apoptosis, autophagy, osteoclastogenesis, and subchondral bone remodeling. Increasing evidence demonstrates that ncRNAs influence multiple OA-associated signaling pathways, particularly NF-κB, TGF-β/SMAD, Wnt/β-catenin, PI3K/Akt, and MAPK/ERK, thereby contributing to cartilage degeneration and the failure of joint homeostasis. This review comprehensively summarizes the current understanding of ncRNA-mediated mechanisms in OA, with an emphasis on mechanistic validation, biomarker development, and therapeutic translation. Among all ncRNA classes, miRNAs currently possess the strongest experimental and translational evidence. miR-140-5p is the most extensively validated cartilage-protective miRNA and suppresses ADAMTS5-mediated extracellular matrix degradation in human OA cartilage, whole-body knockout mouse models, and in vitro systems. Additional miRNAs, including miR-146a, miR-21, and miR-34a, regulate inflammatory signaling, osteoclastogenesis, and chondrocyte survival by modulating NF-κB and TGF-β-related pathways. In contrast, many lncRNAs and circRNAs, including HOTAIR, MALAT1, NEAT1, and ciRS-7, remain predominantly supported by transcriptomic profiling and cell-based studies, with comparatively limited validation in primary human OA tissues. The review further highlights the emerging diagnostic potential of circulating ncRNAs detectable in serum, plasma, and synovial fluid as minimally invasive biomarkers for OA. However, current biomarker studies remain constrained by methodological heterogeneity, small cohort sizes, and a lack of longitudinal validation. In addition, recent advances in ncRNA-based therapeutics, including miRNA mimics, antagomiRs, antisense oligonucleotides, siRNA platforms, nanoparticle carriers, and exosome-mediated delivery systems, are critically discussed. Although these approaches demonstrate encouraging cartilage-protective and anti-inflammatory effects in preclinical OA models, substantial challenges related to delivery efficiency, tissue specificity, long-term safety, and clinical translation remain unresolved. Overall, ncRNAs represent promising molecular regulators and potential therapeutic targets that may contribute to future precision medicine strategies for managing OA.
