In conclusion, our study provides a novel insight into the specific role of DIM on TNF-dependent arthritogenesis, offering ex vivo and in vivo evidence on DIM functions in regulating the proliferation, migration and invasion of RA-FLSs by inhibiting the MAPK and AKT/mTOR pathway and ameliorating arthritis severity and pathological outcome in an AIA model. Here, AKT1 is linked to rheumatoid arthritis.