Circular RNAs orchestrate molecular networks in osteoarthritis: From miRNA sponging to epigenetic and exosome-mediated regulation.

Osteoarthritis (OA) is a progressive degenerative joint disorder characterized by cartilage breakdown, chronic inflammation, and impaired tissue homeostasis, representing a major global health burden with limited disease-modifying therapies. In recent years, circular RNAs (circRNAs), a class of covalently closed non-coding RNAs, have emerged as critical regulators of gene expression in OA pathogenesis. Due to their high stability, tissue specificity, and evolutionary conservation, circRNAs have attracted increasing attention as key molecular modulators of cartilage homeostasis and potential therapeutic targets. This review comprehensively summarizes current advances in the molecular mechanisms of circRNAs in OA, with a particular focus on their roles as competing endogenous RNAs (ceRNAs), epigenetic regulators, and mediators of intercellular communication via exosomes. Current evidence indicates that circRNAs participate in multiple pathological processes associated with OA, including extracellular matrix (ECM) degradation, chondrocyte apoptosis, autophagy dysfunction, inflammatory signaling, and mitochondrial stress, primarily through modulation of signaling pathways such as NF-κB, PI3K/AKT, PTEN, and SIRT. Emerging evidence further highlights their involvement in epigenetic regulation via DNA methylation machinery and their participation in exosome-mediated intercellular communication within the joint microenvironment. Importantly, circRNAs exhibit dual functional roles, acting either as pathogenic amplifiers of cartilage degeneration or as protective regulators that promote chondrocyte survival and tissue repair. This functional versatility underscores their potential as both diagnostic biomarkers and therapeutic targets in OA. Moreover, advances in extracellular vesicle-based delivery systems and synthetic RNA engineering provide promising strategies for translating circRNA biology into clinical applications. Despite these advances, challenges remain regarding mechanistic complexity, tissue-specific functions, and efficient in vivo delivery systems. A deeper understanding of circRNA regulatory networks may facilitate the development of next-generation RNA-based precision therapies for osteoarthritis.