GUF1 encodes a mitochondrial GTPase that functions as an elongation factor promoting mitochondrial protein synthesis. 1 The protein binds to mitochondrial ribosomes in a GTP-dependent manner and acts as a fidelity factor by remobilizing stuck ribosomes and transiently inhibiting elongation to optimize translation accuracy. 1 GUF1-deficient mitochondria exhibit cold- and heat-sensitive growth defects with impaired protein synthesis at low temperatures and defective cytochrome oxidase assembly at elevated temperatures, particularly under nutrient-limiting conditions. 1 GUF1 mutations cause developmental epileptic encephalopathy 40, with a reported homozygous variant (p.Ala609Ser) identified in West syndrome patients presenting with infantile spasms and developmental regression. 2 The mutation affects a conserved alanine within the tRNA-binding domain, impairing GUF1 activity in suboptimal environments and potentially disrupting respiratory chain assembly. 2 Additionally, GUF1 expression correlates with cancer prognosis; reduced GUF1 expression negatively correlates with thyroid cancer prognosis, 3 while elevated GUF1 expression in gastric cancer correlates with poor prognosis and enhanced cell proliferation and migration. 4 GUF1 methylation patterns also show associations with colorectal cancer liver metastasis risk. 5