YTH N6-methyladenosine RNA binding protein 2 mediated m⁶A modification of circHIPK2 promotes cellular senescence and osteoarthritis progression by inhibiting autophagy

N6-methyladenosine (m⁶A) modification has emerged as a critical post-transcriptional regulatory mechanism in osteoarthritis (OA). However, the contribution of m⁶A-dependent regulation of circular RNAs (circRNAs) to chondrocyte senescence and OA progression remains poorly understood. We aimed to elucidate whether m⁶A-mediated control of circRNAs regulates chondrocyte senescence and to define the underlying molecular mechanisms contributing to OA progression. Here, we identified an OA-associated circRNA, circHIPK2, and demonstrated that its abundance and function are regulated by an m⁶A reader-dependent decay mechanism. circHIPK2 expression was reduced in human OA cartilage, and its depletion exacerbated chondrocyte senescence, increased senescence-associated secretory phenotype (SASP) gene expression, and impaired autophagy both in vitro and in the destabilization of the medial meniscus (DMM) model. Mechanistically, YTH N⁶-methyladenosine RNA-binding protein 2 (YTHDF2) recognized m⁶A-modified circHIPK2 and facilitated its degradation, thereby reducing circHIPK2 stability. Functionally, circHIPK2 directly interacted with RAB22A. Loss of circHIPK2 weakened this interaction, enhanced RAB22A-PI3K association, activated the PI3K-AKT-mTOR signaling pathway, disrupted autophagic flux, and accelerated senescence-associated phenotypes. Notably, the protective effects of circHIPK2 were abolished in RAB22A-binding-deficient circHIPK2 mutants, establishing a direct link between molecular interaction and functional outcome. Furthermore, we encapsulated circHIPK2 into lipid nanoparticles (circHIPK2-LNP) for transient intra-articular delivery. Intra-articular administration of circHIPK2-LNP attenuated chondrocyte senescence and alleviated OA progression in DMM mice. Collectively, m⁶A-dependent YTHDF2-mediated degradation of circHIPK2 promotes chondrocyte senescence and OA progression by disrupting autophagy, identifying circHIPK2 as a potential therapeutic target and prognostic biomarker for cartilage aging in OA.