EIF5A (eukaryotic translation initiation factor 5A) is a highly conserved translation regulator with multiple essential cellular functions. Primary Function: EIF5A functions globally in translation elongation and termination, promoting the translation of sequences with structural constraints and increasing the rate of peptidyl-tRNA hydrolysis more than 17-fold 1. Its activity requires post-translational hypusination, a unique modification catalyzed by deoxyhypusine synthase and deoxyhypusine hydroxylase 2. Mechanism: Hypusinated eIF5A (eIF5AHyp) alleviates ribosome pauses at amino acid motifs causing structural constraints and facilitates translation initiation and termination 2. EIF5A also serves as a cellular cofactor for retroviral proteins, including HIV-1 Rev and HTLV-1 Rex, essential for retroviral mRNA export [UniProt]. Additionally, eIF5A mediates spermidine-dependent autophagy activation and longevity through the polyamine-hypusination axis 3. Disease Relevance: Homozygous deletion of EIF5A or hypusination pathway components causes embryonic lethality, while heterozygous variants associate with rare neurodevelopmental disorders 2. EIF5A depletion occurs in Huntington's disease brains, causing ribosome pausing and ribotoxic stress 4. The eIF5A2 isoform is highly expressed in many cancers and designated a candidate oncogene 5. Clinical Significance: eIF5AHyp expression levels carry unfavorable prognostic implications in several cancers and serve as biomarkers 5. Dietary spermidine supplementation enhances eIF5A hypusination, improving cognitive function and mitochondrial health in aging 6. Aspartate-driven eIF5A hypusination promotes lung metastasis aggressiveness 7.