MDM4 is a critical negative regulator of the p53 tumor suppressor pathway. As a p53-interacting protein, MDM4 inhibits p53-mediated cell cycle arrest and apoptosis by binding to p53's transcriptional activation domain, thereby blocking downstream target gene expression 1. MDM4 also stabilizes MDM2 protein and can reverse MDM2-targeted p53 degradation while maintaining p53 transactivation suppression 2. In cancer development, MDM4 is frequently amplified and overexpressed; trisomy of chromosome 1, which increases MDM4 expression, is required for malignant growth and mutually exclusive with TP53 mutations, suggesting "aneuploidy addiction" in cancer cells 3. In p53-mutant colon cancer, MDM4 overexpression inhibits ferroptosis by stabilizing GPX4 through TRIM21-mediated ubiquitination regulation, promoting chemotherapy resistance and cancer progression 4. Under nucleolar stress, ribosomal protein L22 promotes MDM4 exon 6 skipping, reducing full-length MDM4 levels and restoring p53 activity 5. MDM4 gene polymorphisms, particularly rs4245739, show associations with cancer risk in specific populations 6. These mechanisms identify MDM4 as an attractive therapeutic target through MDM4-p53 interaction disruptors to restore p53 anti-tumor activity.