And natural killer cells were reported associated with obesity and other metabolic diseases, such as diabetes. However, in our study, we didn��t find the shared DEGs involved in natural killer cells signaling between these two disorders, although it was the commonly shared pathway in both RA and T2D. IL-17A and IL-17F are primarily produced by a subset of T cells called Th17and are highly homologous, which have been linked to cytokine and chemokine production in various inflammatory and/or auto immune diseases, such asRA.IL-17Aand IL-17F was reported elevated in the synovial tissues or plasma of patients with RA and MNS inhibited adipocyte differentiation in T2D. Differential regulation of cytokine production in intestinal epithelial cells by IL-17A and IL-17F was found shared in both RA and T2D in our study, even without shared DEGs. In this point, we speculated this two pathways involved in immune response was theaetiopatho genesis commonality of RA and T2D, which needs further study for verification. Imipramine hydrochloride Furthermore, 5 upstream regulators predicted to be activated in both RA and T2D in this study, and the common networks shared by them between RA andT2D were identified by the IPA platform: TGM2, NF-��B,p38 MAPK, TNF and CEBPA. Most of the shared DEGs were regulated bythese5 regulators leading to the immune response at the end, such as CYP4F3, DEFA4, DEFA1, MMP8, MMP9, MT2A, ITGB4, RBP1, SNAI1, ARG1, MPO and LTF. Among these genes, MT2A, ITGB4, RBP1 and SNAI1 were down-regulated, the others were up-regulated. TGM2, transglutaminase 2,was the most important regulators in this study with the highest activation z-score among all the upstream regulators in both RA and T2D.As a multi-functional enzyme, the protein encoded by this gene acts as a monomer, which is induced by retinoic acid and appears to be involved in apoptosis. Missense mutations in theTGM2 gene encoding transglutaminase 2are found in patients with early-onset type 2 diabetes, but little reports found the relation between TGM2 and RA.As we know, regulators p38 MAPK, TNF and NF-��B play important roles in transducing inflammation, by which several transcription factors can be directly phosphorylated and activated to bring about pro-inflammatory factors in RA, T2D and other inflammatory or immune diseases, and some of them had already been used as drug targets curing RA orT2D, such as the TNF inhibitors.