MED4 is a core component of the Mediator complex, a coactivator essential for regulated transcription of RNA polymerase II-dependent genes 1. MED4 functions as part of the Mediator scaffold that bridges gene-specific regulatory proteins to RNA polymerase II and general transcription factors, facilitating preinitiation complex assembly 2. Structurally, MED4 forms defined interactions with the RNA polymerase II C-terminal domain, with two CTD peptide regions binding between Mediator modules involving Med4 2. Clinically, MED4 has emerged as a critical survival factor in retinoblastoma; RB1-deficient retinoblastoma cells cannot survive without MED4 both in vitro and in vivo, explaining the paradoxically low tumor penetrance in patients with large RB1 deletions that coincidentally encompass MED4 3. This identifies MED4 as a synthetic lethal target in RB1-inactivated tumors. Additionally, MED4 was identified as a causal risk factor for vascular dementia through Mendelian randomization analysis (OR = 1.819, 95% CI: 1.493-2.217), with the strongest association among identified plasma protein biomarkers 4. MED4 expression was significantly reduced in experimental vascular dementia models, validating its pathogenic role 4. In cervical cancer, MED4 on chromosome 13 correlated with chemoradioresistance at both gene dosage and expression levels 5, suggesting therapeutic potential in multiple malignancies.