DPH2 (diphthamide biosynthesis 2) is essential for the first step of diphthamide synthesis, a critical post-translational modification of elongation factor 2 (eEF2) that occurs across eukaryotes 1. DPH2 functions as part of a heterodimeric complex with DPH1, forming a non-canonical radical SAM enzyme that transfers a 3-amino-3-carboxypropyl (ACP) group from S-adenosyl-L-methionine to a histidine residue on eEF2 2. The protein facilitates reduction of the catalytic iron-sulfur cluster in the DPH1 subunit and localizes to the cytosol 3. Loss-of-function mutations in DPH2 cause diphthamide deficiency syndrome, an autosomal-recessive disorder characterized by intellectual disability, developmental abnormalities, seizures, and craniofacial dysmorphisms 1. Functionally compromised DPH2 variants, including H105P and C341Y, have been identified as disease-susceptibility alleles 1. Beyond developmental roles, DPH2 shows altered expression patterns in various cancers and may serve as a prognostic biomarker, with high expression associated with poor outcomes in hepatocellular carcinoma and other tumor types 45. The protein's role in maintaining translational fidelity makes it crucial for cellular stress responses and growth regulation.