Identified YY1 was over-expressed in RA patients and CIA mice firstly. Blocking YY1 ameliorated disease progression in CIA mice. Blocking YY1 inhibited IL-6 signaling and JAK/Stat signaling pathway. YY1 regulated Th17 and Treg balance via IL-6 signaling pathway in RA. YY1 positively regulated IL-6 transcription by binding to the promoter region of the IL-6.