Unveiling the role of p53 in the pathogenesis and treatment of autoimmune rheumatic diseases.

p53 is a master transcription factor best known for its tumor-suppressing properties. However, its significance extends beyond cancer to the pathogenesis of autoimmune diseases. In addition to its classic effects on the cell cycle and apoptosis, mounting evidence reveals that p53 exerts various non-classical functions, including regulating immunological responses, inflammation, angiogenesis, fibrosis, and other programmed cell death modalities such as ferroptosis. Thus, p53 is critical for maintaining homeostasis and immune tolerance. Dysregulations of p53, including altered expression and mutations in individuals with autoimmune diseases, may contribute to aberrant immune responses, chronic inflammation, organ damage, and disease progression. In this review, we first briefly discuss the canonical and non-canonical functions of p53 and then explore these functions in autoimmune rheumatic disorders. The aim is to illuminate underexplored areas to guide future research that will enhance our understanding of the pathogenesis of these diseases, focusing on rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc). Lastly, we will discuss the potential of p53-based therapies, such as p53 activators, to restore normal p53 activity in autoimmune diseases, which could transform treatment options for these chronic and refractory conditions.