DPH7 (diphthamide biosynthesis 7) catalyzes a critical demethylation step in diphthamide biosynthesis, converting methylated diphthine to diphthine 1. This enzyme functions as a methylesterase that operates between reactions catalyzed by DPH5 and DPH6 in the multi-step pathway generating diphthamide, a post-translational modification of histidine residue 715 on translation elongation factor 2 (eEF2) 1. Diphthamide is essential for translational fidelity and normal protein synthesis in eukaryotes 2. The modification represents the molecular target of bacterial ADP-ribosylating toxins including diphtheria toxin and Pseudomonas exotoxin A 3. Loss of diphthamide biosynthesis, whether through DPH gene inactivation, renders cells resistant to these toxins but paradoxically hypersensitizes cells to TNF-mediated apoptosis through pre-activation of NF-κB and death receptor pathways 3. Clinically, DPH7 variants and mutations in the diphthamide biosynthesis pathway cause autosomal-recessive diphthamide deficiency syndrome, presenting with intellectual disability, developmental abnormalities, and seizures 4. Additionally, DPH7-PTP4A3 fusion genes have been identified in endometrial cancer, correlating with advanced disease stage, higher grade, and recurrence 5. DPH7 is also implicated as a Vif-dependent HIV target in infected primary CD4+ T cells 6.