EIF2B4 encodes the delta subunit of the eukaryotic translation initiation factor 2B (eIF2B) complex, a guanine nucleotide exchange factor (GEF) that catalyzes GDP-to-GTP exchange on eIF2 gamma to initiate translation 123. This GEF activity is repressed when eIF2 is phosphorylated on its alpha subunit, thereby restricting methionyl-initiator tRNA availability and globally suppressing translation 13. In hepatocellular carcinoma (HCC), EIF2B4 is significantly upregulated and promotes tumorigenesis through GEF-dependent enhancement of STAT3 protein translation, independent of mRNA level changes 4. EIF2B4-driven STAT3 translation facilitates HCC progression, immune evasion, and resistance to anti-PD-1 immunotherapy, while EIF2B4 knockout restores antitumor immunity 4. Clinically, EIF2B4 mutations cause vanishing white matter disease (VWM/CACH syndrome), an autosomal recessive leukodystrophy characterized by progressive white matter rarefaction and cerebrospinal fluid replacement 56. A subtype, ovarioleukodystrophy, combines white matter degeneration with primary ovarian insufficiency 78. EIF2B4 variants are also identified as potential genetic risk factors in premature ovarian insufficiency 9. Neurological manifestations include ataxia, spasticity, cognitive impairment, epilepsy, and episodes of acute regression following infections or head trauma 610.