A New N6-Methyladenosine Inhibitor, Celastrol, Alleviates Rheumatoid Arthritis via Targeting IGF2BP3.

The proliferation of fibroblast-like synoviocytes (FLS) and macrophage-mediated inflammation are the main clinical features of rheumatoid arthritis (RA). Studies showed that insulin-like growth factor-2 mRNA binding protein-3 (IGF2BP3) may be involved in regulating the biological functions of different immune cells and FLS. Therefore, the identification of drugs that target IGF2BP3 has important clinical significance for improving RA. Molecular docking and surface plasmon resonance (SPR) analyses were used to identify a small molecule compound targeting IGF2BP3, celastrol (CEL). We subsequently examined the effects of CEL on RAW264.7 cells and FLS. IGF2BP3 knockout (KO) arthritis mice were used to identify the targets and mechanism of CEL in relieving RA. We found that CEL could bind to IGF2BP3 closely and reduce its expression. Additionally, CEL not only inhibited RA-FLS proliferation but also decreased the inflammatory activation of macrophages. The IGF2BP3-RASGRF1-mTORC1 was critical for CEL-mediated amelioration of RA. KO-IGF2BP3 arthritis mice further showed that the protective effect of CEL against arthritis depended on IGF2BP3. Collectively, this study revealed that CEL inhibited the IGF2BP3/RASGRF1/mTORC1 axis to reduce cell proliferation and inflammatory activation, thereby alleviating the progression of RA. Our study suggests that clinical attention should be given to IGF2BP3 inhibitors, such as CEL.