Insights into Cellular Mechanisms and Treatment Strategies of p53 in Multiple Sclerosis: A Systematic Review

The tumor suppressor p53 modulates key cellular processes such as apoptosis, oxidative stress, and immune regulation that are increased in multiple sclerosis (MS) pathology. This systematic review is on preclinical evidence on p53’s role in MS animal models and evaluates therapeutic strategies targeting p53. Following PRISMA guidelines, we searched PubMed, Google Scholar, Scopus, and Web of Science (January 2000–September 2025) for original English language studies assessing p53 functions in MS animal models. Study quality was appraised using the SYRCLE risk of bias tool. From 1,432 records, 415 duplicates were removed; 1,017 titles were screened, 70 full texts assessed, and 26 studies included. Seventeen studies focused on apoptosis, nine on oxidative stress and neuroprotection, and four on other p53 mediated mechanisms. Experimental models included experimental autoimmune encephalomyelitis (EAE), cuprizone-induced demyelination, ethidium bromide models, and transgenic/mutant strains. Key findings indicate that p53 up regulation worsens neuronal and oligodendrocyte apoptosis (via Bax/Bcl-2 imbalance, caspase activation), while genetic or pharmacological p53 inhibition leads to neuroprotection and supports remyelination. SYRCLE assessment revealed generally adequate random sequence generation and baseline reporting, but frequent omissions in allocation concealment and blinding of caregivers/outcome assessors. Preclinical evidence highlights p53 as an important controller of multiple procedures relevant to MS pathology, including apoptosis, oxidative stress, immune balance, and remyelination. Small molecule inhibitors, dietary interventions, and stem cell secretome demonstrate potential to modulate p53 driven pathways, mitigate neurodegeneration, and rebalance immune responses. These findings suggest that therapeutic strategies targeting p53 pathways hold promise for mitigating neurodegeneration and promoting neuroprotection in MS.