Objective To explore the mechanism of triptolide (TP) in the treatment of rheumatoid arthritis (RA) from the perspective of regulating lipid metabolism. Methods The arthritis rat model was induced by injecting bovine type Ⅱ collagen and incomplete Freund's adjuvant. After successful modeling,rats were divided into the normal group,model group,and TP group. After 21 days of treatment,the therapeutic effects of TP on collagen-induced arthritis ( CIA) rats were assessed by using arthritis index ( AI) scores,serum inflammatory factor assay,and HE staining of ankle joints.Targeted metabolomics was used to measure the levels of fatty acids (FAs) in the bone tissue of rats ankle joint. RT-qPCR and Western blot were used to assess the expression of fatty acid synthase (FASN) in the bone tissue of ankle joint,and molecular docking and surface plasmon resonance ( SPR) assays was used to test the binding sites and affinity between FASN and TP. Results Compared with the model group,TP could improve joint swelling,decrease the AI score of CIA rats(P<0. 05),lower serum tumor necrosis factor ( TNF)-α,interleukin ( IL)-6,and IL-1β levels ( P<0. 05),alleviate inflammatory cell infiltration of joints,synovial tissue hyperplasia,and joint cavity stenosis. Targeted metabolomics results showed that compared with the normal group,the levels of pentadecanoic acid ( C15:0),palmitic acid ( C16:0),heptadecanoic acid (C17:0),stearic acid (C18:0),linolaic acid (C18:2),and α-linolenic acid (C18:3) were elevated in the bone tissue of rats ankle joint of the model group ( P<0. 05),while dodecenoic acid ( C12:1) was decreased (P<0. 05). Compared with the model group,the levels of C12:1 elevated (P<0. 05),while tetradecenoic acid(C14:1),C15:0,and C16:0 decreased in the bone tissue of rats ankle joint of TP group (P<0. 05). RT-qPCR and Western blot results demonstrated that,compared to the normal group,FASN mRNA and protein expression were significantly increased in the bone tissue of rats ankle joint of the model group (P<0. 05). Compared with the model group,both FASN mRNA and protein expression were markedly down-regulated in the bone tissue of rats ankle joint of the TP group (P<0. 05).Molecular docking and SPR results revealed a strong binding affinity and high affinity between FASN and TP. Conclusion TP may treat RA by regulating lipid metabolism,and FASN may be one of its therapeutic targets for RA.
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