How p53 Drives and Could Treat Autoimmune Rheumatic Diseases

A protein famous for preventing cancer may also help explain why the immune system turns against the body in rheumatoid arthritis, lupus and systemic sclerosis. A new review in Molecular Biology Reports presents p53 as a central regulator of autoimmune rheumatic disease, expanding its familiar identity as the “guardian of the genome” into a broader role in immune tolerance, inflammation, tissue repair and cell death. The review examines how disturbances in p53 activity could allow immune reactions to persist, intensify chronic inflammation and accelerate organ damage. It also explores whether medicines designed to restore or activate p53 might eventually provide new treatment strategies for chronic diseases that remain difficult to control. The work is a review rather than a clinical trial, so it does not demonstrate that p53-targeting drugs are ready for patients. Instead, it brings together evidence from molecular studies, animal models and observations in people to identify a possible therapeutic connection between cancer biology and rheumatology.

p53 is produced from the TP53 gene and functions primarily as a transcription factor, a protein that binds DNA and changes the activity of other genes. Under normal conditions, p53 levels are kept relatively low, but cellular stress—including DNA damage, abnormal growth signals and metabolic disruption—can stabilize the protein. Once activated, p53 can pause the cell cycle, giving the cell time to repair damaged DNA. If the damage is too severe, it can trigger apoptosis, a controlled form of cellular suicide that removes potentially dangerous cells. These functions explain p53’s long-standing reputation as a tumor suppressor. Yet p53 is not simply an emergency brake for cell division. Its activity is shaped by a network of regulators, including MDM2, and it influences metabolism, cellular senescence, inflammatory signaling and several forms of programmed cell death. The review argues that these “non-canonical” functions are crucial to understanding autoimmune disease, where the central problem is not uncontrolled cancerous growth but a failure to maintain immune restraint.

Immune tolerance depends on the ability to eliminate or control cells that recognize the body’s own tissues. T cells and B cells must be activated strongly enough to fight infections, but they must also be restrained when their targets are self-proteins. p53 appears to participate in this balancing act at several levels. T-cell receptor signaling can temporarily reduce p53 activity to support antigen-specific CD4-positive T-cell responses, while other evidence suggests that activating p53 can promote regulatory T cells, or Tregs, which suppress excessive immune reactions. The balance between inflammatory T helper 17 cells and Tregs is particularly important in autoimmune rheumatic disorders. Too much Th17 activity can sustain tissue inflammation, whereas inadequate Treg function can weaken immune tolerance. By affecting transcription, cell survival and signaling pathways such as STAT, p53 may help determine which side of this balance dominates. Its influence is therefore highly context-dependent: the same protein can support immune activation in one setting and immune suppression in another, depending on the cell type, stress signal and molecular partners involved.

The review places rheumatoid arthritis at the forefront of this proposed mechanism. In the disease, the synovium—the specialized tissue lining the joints—becomes chronically inflamed and thickened. Fibroblast-like synoviocytes, which normally help maintain the joint environment, can acquire aggressive properties, invading cartilage and contributing to bone destruction. Studies discussed in the review have reported altered p53 expression, p53 overproduction and TP53 mutations in subsets of rheumatoid arthritis synovial tissue. These changes may affect whether abnormal synovial cells undergo apoptosis or continue to proliferate and release inflammatory mediators. p53 also interacts with nuclear factor κB, or NF-κB, a major transcriptional driver of inflammatory gene expression. The relationship is not one-directional: inflammatory signals can modify p53, while p53 can influence NF-κB activity and the production of cytokines such as interleukin-6. This molecular cross-talk could help explain why inflammation becomes self-sustaining inside the joint. Evidence from animal models further suggests that p53 can regulate arthritis severity through both local synovial mechanisms and adaptive immune responses.

A second route involves the Th17–Treg system. Experimental work summarized by the authors indicates that p53 can influence STAT-mediated signaling, thereby affecting the differentiation and function of these opposing T-cell populations. When p53 regulation is disturbed, the immune system may favor inflammatory Th17 cells over protective Tregs, creating conditions for persistent joint inflammation. p53 also appears to affect synovial fibroblasts directly. In some experiments, restoring or enhancing p53 activity reduced inflammatory behavior, limited invasive growth and promoted apoptosis in fibroblast-like synoviocytes. Other studies have identified molecular circuits involving microRNAs, including a p53–microRNA-22–Cyr61 axis, that regulate interleukin-6 production and Th17 differentiation. Meanwhile, extracellular vesicles released by rheumatoid arthritis synovial fibroblasts may alter blood-vessel growth by affecting p53 and mTOR signaling in endothelial cells. This is important because angiogenesis—the formation of new blood vessels—helps supply the expanding inflamed synovium with oxygen and immune cells. The review presents these findings as interconnected mechanisms rather than a single pathway, with p53 positioned at the intersection of cell survival, cytokine production, immune-cell programming and vascular remodeling.

Systemic lupus erythematosus, or SLE, provides a different example of how p53 may influence autoimmunity. Lupus can affect the skin, joints, kidneys, blood vessels and nervous system, and is characterized by the production of antibodies against components of the body’s own cells. The review describes evidence of altered p53 expression and anti-p53 autoantibodies in people with lupus and other rheumatic diseases. In experimental lupus, immune responses against the C-terminal region of p53 have been associated with recognition of damaged DNA, linking p53-related autoimmunity to one of lupus’s defining features: the generation of antibodies against nuclear material. Studies in mice have also implicated p53 in spontaneous autoantibody production. Loss of p53 or disruption of its downstream pathways can affect B-cell activation, Treg biology and the development of lupus-like disease. The review highlights a recent line of investigation in which p53 deficiency reprogrammed propionyl-CoA metabolism and histone modifications in Tregs, suggesting that p53 may regulate immune tolerance through epigenetic and metabolic mechanisms as well as through direct gene transcription. These findings remain mechanistic and experimental, but they suggest that p53 dysfunction could contribute to lupus at multiple stages of the immune response.

The review also examines systemic sclerosis, a disease in which immune abnormalities, vascular injury and progressive fibrosis combine to harden the skin and damage internal organs. Fibrosis occurs when activated fibroblasts produce excessive extracellular matrix, particularly collagen, causing tissues to become stiff and scarred. Increased p53 and p21, a p53-associated cell-cycle inhibitor, have been observed in experimental scleroderma skin. Anti-p53 autoantibodies have also been reported in systemic sclerosis and overlap syndromes. However, the evidence is more complicated than a simple model in which p53 mutations cause the disease. Studies cited in the review found no p53 gene mutations in some skin fibroblasts from patients, while other work reported normal transcription-level expression of p53 and the apoptosis-related protein PUMA. This apparent inconsistency may mean that p53 function is altered through protein stability, chemical modification, cellular localization or interactions with other signaling systems rather than through mutations in the gene itself. Because p53 can influence senescence, inflammation, angiogenesis and fibrotic responses, even subtle changes in its regulation could affect how injured tissue heals—or whether repair becomes pathological scarring.

One particularly promising but complex theme is ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation. Unlike apoptosis, ferroptosis involves the accumulation of toxic oxidized membrane lipids when antioxidant defenses fail. A key protective system includes SLC7A11, a transporter that helps cells import cystine for production of glutathione, a major intracellular antioxidant. p53 can regulate this pathway, sometimes promoting ferroptosis by suppressing SLC7A11 and sometimes protecting cells, depending on the cellular context and intensity of stress. In autoimmune disease, ferroptosis could have opposing effects. Removing harmful immune cells might reduce disease activity, but uncontrolled ferroptosis in healthy tissue could intensify inflammation and organ injury. The review points to studies in rheumatoid arthritis in which sulfasalazine promoted ferroptosis through pathways involving p53, SLC7A11, AKT and ERK1/2. In lupus-prone mice, the compound CX-5461 reportedly improved disease by triggering ferroptosis in B cells through a p53–SLC7A11–ALOX12 pathway. These findings raise the possibility of selectively targeting ferroptosis in pathogenic immune cells, although translating such results into safe human treatments will require precise control over cell type, dose and tissue distribution.

The therapeutic implications are attracting attention because existing treatments for rheumatoid arthritis, lupus and systemic sclerosis do not work equally well for everyone, and some patients develop drug resistance or progressive organ damage. A p53-based strategy could theoretically take several forms: activating normal p53, restoring the function of certain mutant forms, blocking negative regulators such as MDM2, or using small RNAs, extracellular vesicles or cell therapies to reshape p53 signaling in specific tissues. Compounds that reactivate mutant p53 have already been investigated in cancer and, according to the review, the mutant-p53 reactivator PRIMA-1MET reduced inflammatory signaling in rheumatoid arthritis fibroblast-like synoviocytes by inhibiting NF-κB. Stem-cell-derived extracellular vesicles have likewise been studied as vehicles capable of delivering regulatory molecules that affect p53 pathways. But the biology creates substantial hazards. Excessive p53 activation can cause widespread apoptosis, senescence or tissue injury, while suppressing p53 could weaken tumor surveillance and increase cancer risk. The protein’s effects also vary between immune cells, fibroblasts, endothelial cells and epithelial tissues. The authors therefore frame p53 activators and related interventions as a research direction, not an established treatment. Future studies must determine which patients have p53-related disease mechanisms, which tissues should be targeted and how immune tolerance can be restored without compromising the protein’s essential role in cancer prevention. Akbarzadeh, F., Farhadi, E., Vodjgani, M., Jamshidi, A., & Mahmoudi, M. (2026). Unveiling the role of p53 in the pathogenesis and treatment of autoimmune rheumatic diseases. Molecular Biology Reports, 53, Article 1483. https://doi.org/10.1007/s11033-026-12666-1