MAP3K6 (mitogen-activated protein kinase kinase kinase 6) is a serine/threonine protein kinase that functions as a component of signal transduction cascades, selectively activating the JNK pathway while not affecting ERK or p38 kinase pathways [UniProt]. The protein exhibits catalytic activity through ATP binding and magnesium ion binding, facilitating protein phosphorylation in response to cellular signals. Regarding disease relevance, MAP3K6 has emerged as a candidate gastric cancer predisposition gene. Initial studies identified germline MAP3K6 variants (p.P946L, p.F849Sfs*142, p.P958T, p.D200Y, p.V207G) in families with familial gastric cancer without CDH1 mutations, with evidence of somatic second-hit mutations and DNA hypermethylation in tumor specimens 1. However, subsequent large-scale screening revealed that deleterious MAP3K6 variants occur frequently in the general population, substantially diminishing its classification as a specific gastric cancer predisposition gene 2. MAP3K6 mutations have also been detected in mixed-phenotype acute leukemia cases 3 and basal ganglia calcification with neurological manifestations 4. Clinically, MAP3K6 regulates vascular endothelial growth factor (VEGF) expression under both normoxic and hypoxic conditions, with MAP3K6 downregulation suppressing tumor angiogenesis and growth 5. Therapeutic inhibition of MAP3K6 has shown promise in gastric cancer cell models, where salidroside-mediated MAP3K6 downregulation induced apoptosis and cell cycle arrest 6.