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

TL;DR

This study shows that a specific RNA modification promotes cartilage cell aging and osteoarthritis by disrupting a cellular cleanup process called autophagy.

Contribution

Identifies circHIPK2 as a novel m6A-regulated circRNA that inhibits autophagy and accelerates osteoarthritis through YTHDF2-mediated degradation.

Findings

circHIPK2 levels are reduced in osteoarthritis cartilage and its loss worsens chondrocyte aging and autophagy impairment.

YTHDF2 binds m6A-modified circHIPK2, promoting its degradation and triggering senescence via the PI3K–AKT–mTOR pathway.

Delivery of circHIPK2 via lipid nanoparticles reduces chondrocyte senescence and slows osteoarthritis progression in mice.

Abstract

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.

The online version contains supplementary material available at 10.1186/s43556-026-00441-4.

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