2. Academic Validation
  3. CircTspan3 Promotes Cartilage Development Through ANNEXIN A2-Mediated Ferroptosis and Apoptosis Inhibition and Exosome-Mediated Paracrine Signaling

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

  • Adv Sci (Weinh). 2026 Feb;13(10):e13418. doi: 10.1002/advs.202513418.
Yiming Pan 1,  Fengmei Zhang 1,  Jiayan Zhong 1,  Qian Gong 1,  Nana Geng 1,  Biao Kuang 2,  Qiumei Lan 1,  Miao Yi 1,  Qiqi Zeng 1,  Cheng Chen 3,  Mengtian Fan 1,  Chunliang Zhao 4,  Deping Zeng 4,  Yu Du 2,  Mao Nie 2,  Zhibiao Wang 4,  Fengjin Guo 1
Affiliations

Affiliations

  • 1 Department of Orthopedics, State Key Laboratory of Ultrasound in Medicine and Engineering, School of Basic Medical Sciences, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China.
  • 2 Department of Orthopedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China.
  • 3 Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China.
  • 4 State Key Laboratory of Ultrasound in Medicine and Engineering, Chongqing Medical University, Chongqing, China.
PMID: 41486887 DOI: 10.1002/advs.202513418
Abstract

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.

Keywords

ANXA2; P‐ANXA2 (Ser26); Xbp1s; apoptosis; cartilage development; circTspan3; exosomes; ferroptosis.

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