Triptolide inhibits cell growth and inflammatory response of fibroblast-like synoviocytes by modulating hsa-circ-0003353/microRNA-31-5p/CDK1 axis in rheumatoid arthritis

Abstract

Triptolide (TPL) is an active component derived from Tripterygium wilfordii Hook F (TwHF) with therapeutic potential for rheumatoid arthritis (RA). However, the underlying mechanism of TPL is remains under-studied. Competing endogenous RNA (ceRNA) networks may participate in the response to TPL in RA. Herein, we sought to identify a TPL response-related ceRNA axis. A circular RNA (circRNA)-microRNA (miRNA)-mRNA ceRNA axis associated with the TPL response was constructed according to our previous study. Modulatory mechanisms of the ceRNA axis were ascertained through a series of experimentations. The clinical relevance of the ceRNA axis was also determined using computational models. Here, we found that TPL had excellent clinical effect on RA and promising therapeutic efficacy in experimental animals. The ceRNA axis of hsa-circ-0003353 (circ0003353), miR-31-5p, and CDK1 was identified as a candidate biomarker for the response of RA patients to TPL. TPL inhibited the viability, proliferation, and cell cycle entry of RA-fibroblast-like synoviocytes (FLSs), as well as the production of cytokines. Overexpression of circ0003353 abolished the inhibitory effects of TPL on RA-FLSs. Mechanistically, circ0003353 sponged miR-31-5p that inversely targeted CDK1 and manipulated the p21/Cyclin B axis. Additionally, consecutive rescue experiments indicated that the inhibitory impacts of TPL on RA-FLSs were dependent on the circ0003353/miR-31-5p/CDK1 axis. Molecular docking was also applied to predict the specific binding sites and binding capacity of TPL to related targets. In conclusion, the present study demonstrated that TPL repressed the cell growth and inflammatory response of RA-FLSs by mediating the expression of the circ0003353/miR-31-5p/CDK1 axis. This novel ceRNA axis may serve as a biomarker for screening RA patients who respond to TPL treatment, which holds potential applications in the diagnosis and therapy of RA.