Elevated chronic glucose metabolism due to hypoxia and highly pro-inflammatory mediators in the microenvironment of the RA synovium, stimulates and activates important signaling pathways in FLSs, including mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K)/Akt, Janus kinase (JAK)/STAT, and hypoxia-inducible factor (HIF)-1α [49]. This evidence concerns the gene AKT1 and rheumatoid arthritis.