Clematichinenoside AR inhibits the pathology of rheumatoid arthritis by blocking the circPTN/miR-145-5p/FZD4 signal axis

The Traditional Chinese medicine roots and rhizomes of Clematis chinensis Osbeck (CCO) has obvious improvement effect on rheumatoid arthritis (RA). Clematichinenoside AR (CAR) is an effective monomer of CCO and is a potential natural product for the treatment of RA. In this work, we systematically evaluated the therapeutic effect of CAR on RA model mice and its inhibitory effects on FLS proliferation and inflammation in RA. We confirmed that CAR has a good therapeutic effect on RA. CAR interfered with the circPTN/miR-145-5p signal axis by binding the FZD4, and then inhibited the role of Wnt/β-catenin signal pathway in the pathogenesis of RA. CAR has the potential to develop into a therapeutic drug for RA. [Display omitted] •CAR is an effective monomer of roots and rhizomes of Clematis chinensis Osbeck.•CircPTN/miR-145-5p signal axis promotes RA development by inhibiting the FZD4.•CAR interferes with the circPTN/miR-145-5p signal axis by targeting the FZD4.•CircPTN is an inhibitor of miR-145-5p. Traditional Chinese medicine roots and rhizomes of Clematis chinensis Osbeck (CCO) has the effect of improving rheumatoid arthritis (RA), Clematichinenoside AR (CAR) is an effective monomer of CCO and a promising natural product for the treatment of RA. In this work, we aim to systematically evaluate whether CAR can improve RA pathology, inhibit the fibroblast-like synoviocytes (FLS) proliferation and inflammatory response, and further investigate the mechanism of CAR inhibiting RA through molecular docking, molecular dynamics and molecular biology methods. Combined with the research results of CIA mice and FLS from RA patients, we found that CAR significantly improved the severity of CIA mice, and inhibited the proliferation and inflammatory response of FLS. Combined with bioinformatics prediction, we confirmed that circPTN promoted frizzled-4 (FZD4) expression through sponging miR-145-5p, then activating the Wnt/β-catenin pathway. The circPTN/miR-145-5p/FZD4 signal axis was involved in the pathogenesis of RA. Furthermore, CAR blocked the circPTN/miR-145-5p/FZD4 signal axis by combining with FZD4 and improved RA pathology. The circPTN/miR-145-5p/FZD4 signal axis plays an important role in promoting the pathogenesis of RA, and CAR from CCO may inhibit RA pathology by combining the FZD4 and further blocking this signal axis.