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<p>Osteoarthritis (OA) involves oxidative stress-induced chondrocyte senescence and extracellular matrix (ECM) dysregulation, yet disease-modifying therapies remain elusive. This study investigates the effects of cycloastragenol (CAG), a telomerase-activating triterpenoid from Astragalus membranaceus, on OA progression with a focus on NRF2/NF-κB signaling. In vitro, CAG suppressed oxidative stress-induced senescence in primary rat chondrocytes, evidenced by reduced SA-β-gal positivity, partially restored EdU proliferation, and downregulated senescence related proteins expression. In addition, CAG concurrently attenuated senescence-associated secretory phenotype (SASP) and partially restored ECM homeostasis. Mechanistically, molecular docking analysis suggested a potential interaction between CAG and the Kelch domain of KEAP1. Consistent with this, CAG treatment was associated with NRF2 pathway activation and attenuation of TBHP-induced NF-κB signaling. Importantly, genetic inhibition of NRF2 significantly attenuated the protective effects of CAG, supporting a required role for NRF2 in mediating CAG-induced suppression of oxidative stress and inflammatory signaling. In vivo, intra-articular CAG administration in monosodium iodoacetate (MIA)-induced OA rats reduced cartilage degradation, rescued ECM homeostasis, and enhanced NRF2 activation. Collectively, CAG mitigates the degradation of the extracellular matrix and suppresses the senescence-associated secretory phenotype (SASP) induced by osteoarthritis (OA).</p>

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Cycloastragenol attenuates osteoarthritis by restoring chondrocyte senescence via the NRF2/NF-κB signaling axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月12日

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  • Shuhao Zhang,
  • Yanlong Zou,
  • Jundong Long,
  • Yufan Wang,
  • Jian Chen,
  • Miao Teng

摘要

Osteoarthritis (OA) involves oxidative stress-induced chondrocyte senescence and extracellular matrix (ECM) dysregulation, yet disease-modifying therapies remain elusive. This study investigates the effects of cycloastragenol (CAG), a telomerase-activating triterpenoid from Astragalus membranaceus, on OA progression with a focus on NRF2/NF-κB signaling. In vitro, CAG suppressed oxidative stress-induced senescence in primary rat chondrocytes, evidenced by reduced SA-β-gal positivity, partially restored EdU proliferation, and downregulated senescence related proteins expression. In addition, CAG concurrently attenuated senescence-associated secretory phenotype (SASP) and partially restored ECM homeostasis. Mechanistically, molecular docking analysis suggested a potential interaction between CAG and the Kelch domain of KEAP1. Consistent with this, CAG treatment was associated with NRF2 pathway activation and attenuation of TBHP-induced NF-κB signaling. Importantly, genetic inhibition of NRF2 significantly attenuated the protective effects of CAG, supporting a required role for NRF2 in mediating CAG-induced suppression of oxidative stress and inflammatory signaling. In vivo, intra-articular CAG administration in monosodium iodoacetate (MIA)-induced OA rats reduced cartilage degradation, rescued ECM homeostasis, and enhanced NRF2 activation. Collectively, CAG mitigates the degradation of the extracellular matrix and suppresses the senescence-associated secretory phenotype (SASP) induced by osteoarthritis (OA).