HYKK (hydroxylysine kinase) catalyzes the GTP-dependent phosphorylation of 5-hydroxy-L-lysine and functions as an amino acid kinase localized to the mitochondrial matrix. While its primary biochemical role involves hydroxylysine metabolism, recent genetic evidence has revealed disease relevance: HYKK variants are associated with chr15 obstructive pulmonary disease (COPD) susceptibility through regulatory effects on the IREB2 gene locus at chromosome 15.1 1. Specifically, the HYKK rs8034191:T>C variant showed significant association with blood DNA methylation and differential IREB2 expression in lung tissues 1. Most notably, HYKK (also known as AGPHD1) has been identified as a potential therapeutic target for lung squamous cell carcinoma, with consistent genetic associations demonstrated across both discovery and replication cohorts showing increased cancer risk (OR = 1.28, 95% CI = 1.24-1.33) 2. Meta-analytic evidence also supports the HYKK rs931794 variant as significantly associated with lung cancer susceptibility with strong cumulative epidemiological evidence 3. These findings suggest HYKK warrants further investigation as both a mechanistic contributor to respiratory disease and a potential drug target for cancer prevention and treatment.