STX6 (syntaxin-6) is a SNARE protein that mediates intracellular vesicle trafficking, primarily functioning in retrograde transport from early endosomes to the trans-Golgi network and in endocytic recycling pathways 1. It promotes vesicle docking and fusion at target membranes through interactions with other SNARE components 2. STX6 has emerged as a significant genetic risk factor for multiple neurodegenerative diseases. Genome-wide association studies identified STX6 variants as risk loci for sporadic Creutzfeldt-Jakob disease (sCJD), with evidence suggesting increased STX6 expression exacerbates disease pathogenesis 13. Mouse models with Stx6 depletion showed 12-day differences in prion disease incubation periods following RML and ME7 inoculation 1. STX6 also associates with progressive supranuclear palsy risk 4. Multi-omics analysis identified STX6 among five high-evidence therapeutic targets for sCJD, with particularly elevated neuronal expression linked to disease risk 3. Beyond neurodegeneration, STX6 expression correlates with adverse outcomes in hepatocellular carcinoma, where STX6-mediated autophagy confers lenvatinib resistance through interactions with Beclin1, VTI1A, and VAMP3 5. In atherosclerosis, the miR-375-3p/STX6 axis promotes endothelial cell senescence via TGF-beta signaling, with STX6 overexpression reducing disease progression 6. STX6 variants also influence ERBB2-driven breast cancer susceptibility and chemotherapy response 7.