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<p>Cartilage metabolism balance chaos is crucial in the development and progression of osteoarthritis (OA), with chronic low-grade inflammation being the primary factor that leads to chondrocyte metabolic dysregulation. Fexofenadine (FFD) is a widely used commercially available anti-allergy compound, which has been shown to reduce inflammation. The present study finds FFD’s therapeutic effects in primary human ex-vivo cultures and surgically induced murine models. Mechanism study illustrates FFD exhibits chondroprotective effect through anti-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated inflammation and pro-Transforming Growth Factor Beta (TGFβ)-associated anabolism. Specifically, FFD directly binds to cytosolic phospholipase A2 (cPLA2), down-regulating downstream NF-κB activation, resulting in alleviated catabolism. Notably, Signal Transducer and Activator of Transcription 1 (STAT1) is first identified as FFD’s target by Drug affinity responsive target stability which shows the Gln-314 site is required. FFD blocks STAT1 binds to TGF-β type I receptor, leading to secondary SMAD Family Member 2 (Smad2) phorsphorylation, slightly enhances chondrocyte proliferation and matrix production. Importantly, further study demonstrates FFD directly binds Smad2 by the target proteins fishing technique, remarkably active TGFβ-related biological process. These findings provide new insights into the chondroprotective role of FFD with novel target and downstream pathway, offering promising avenues for the treatment of OA.</p><p></p>

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Fexofenadine protects against osteoarthritis by targeting Smad2 and STAT1 to enhance anabolism and binding cPLA2 to inhibit catabolism

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月21日

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  • Kaiwen Liu,
  • Xiaodi Zhang,
  • Bin Ning,
  • Ronghan Liu,
  • Cheng Wang,
  • Lei Cheng,
  • Weiwei Zheng,
  • Jianlu Wei

摘要

Cartilage metabolism balance chaos is crucial in the development and progression of osteoarthritis (OA), with chronic low-grade inflammation being the primary factor that leads to chondrocyte metabolic dysregulation. Fexofenadine (FFD) is a widely used commercially available anti-allergy compound, which has been shown to reduce inflammation. The present study finds FFD’s therapeutic effects in primary human ex-vivo cultures and surgically induced murine models. Mechanism study illustrates FFD exhibits chondroprotective effect through anti-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated inflammation and pro-Transforming Growth Factor Beta (TGFβ)-associated anabolism. Specifically, FFD directly binds to cytosolic phospholipase A2 (cPLA2), down-regulating downstream NF-κB activation, resulting in alleviated catabolism. Notably, Signal Transducer and Activator of Transcription 1 (STAT1) is first identified as FFD’s target by Drug affinity responsive target stability which shows the Gln-314 site is required. FFD blocks STAT1 binds to TGF-β type I receptor, leading to secondary SMAD Family Member 2 (Smad2) phorsphorylation, slightly enhances chondrocyte proliferation and matrix production. Importantly, further study demonstrates FFD directly binds Smad2 by the target proteins fishing technique, remarkably active TGFβ-related biological process. These findings provide new insights into the chondroprotective role of FFD with novel target and downstream pathway, offering promising avenues for the treatment of OA.