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

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. Mechanism of Fexofenadine in treating osteoarthritis. Created with BioRender.com.