Abstract
Rheumatoid arthritis (RA) is a complex disorder that involves the immune system, inflammation, and the growth of abnormal tissue in the joints, causing damage. The development of RA is regulated by important factors such as inflammatory cytokines, active angiogenesis, and oxidative stress, which promote the process of autoimmunity, chronic inflammation, and tissue destruction. Recent studies have shown that activation of p53, a protein that suppresses the growth of tumors, is an ongoing process that commonly occurs during inflammation. This activation contributes to regulating and controlling normal inflammatory responses. Functional mutations in the p53 gene have been detected in the synovial tissue in individuals diagnosed with RA, especially those with severe and destructive illness. These mutations may occur due to persistent inflammation caused by reactive oxygen species (ROS), leading to changes in the genetic material. The overall absence of the p53 leads to elevated hypoxia-inducible factor 1 (HIF-1) alpha subunit levels and enhances HIF-1α-mediated activation of the vascular endothelial growth factor (VEGF) gene in low-oxygen conditions, thereby promoting neovascularization. Furthermore, p53 modulates ROS production via nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), with wild-type p53 inhibiting NOX4 induction, ROS generation, and cellular migration, whereas mutant-p53 enhances NOX4 expression, ROS production and promotes cell migration. This review addresses the importance of p53 in the processes of NADPH oxidase and angiogenesis, both of which are important in developing RA.