CircTspan3 Promotes Cartilage Development Through ANNEXIN A2‐Mediated Ferroptosis and Apoptosis Inhibition and Exosome‐Mediated Paracrine Signaling

Circular RNAs (circRNAs) are covalently closed, stable non-coding RNAs that regulate diverse cellular processes. Here, we identify circTspan3 - derived from exons 2-6 of the Tspan3 gene - as a key regulator of cartilage development. The expression of circTspan3 is significantly downregulated in X-box binding protein 1 (Xbp1) conditional knockout (cKO) mice displaying chondrodysplasia and positively correlates with anabolic markers of cartilage. The XBP1 spliced (XBP1s) transcriptionally upregulates circTspan3, which in turn promotes anabolic activity in chondrocytes while suppressing both apoptosis and ferroptosis. Mechanistically, phosphorylation of ANNEXIN A2 (ANXA2) at Ser26 facilitates the cytoplasmic translocation of circTspan3, where ANXA2 mediates its packaging into exosomes for paracrine signalling. Exosomal circTspan3 enhances growth-plate expansion and effectively repairs cartilage defects in vivo. These findings highlight circTspan3 as a key modulator of growth-plate homeostasis and suggest its translational potential in treating cartilage injury and growth-associated skeletal disorders.