STX5 (syntaxin 5) is a SNARE protein essential for anterograde and retrograde endoplasmic reticulum (ER)-Golgi trafficking in mammalian cells 1. As a key component of the ER-to-Golgi SNARE complex, STX5 mediates vesicle docking and fusion through interactions with cognate SNAREs, regulatory proteins like SCFD1, and membrane tethering complexes 2. STX5 exists as two isoforms generated from alternative translation start sites, with the short isoform specifically required for intra-Golgi transport 2. Beyond canonical vesicle trafficking, STX5 possesses RNA-binding capacity and regulates miRNA export from activated macrophages, facilitating inflammatory cytokine expression and pathogen clearance 3. STX5 determines Golgi architecture and regulates von Willebrand factor secretion through control of Weibel-Palade body morphology 4. Clinically, STX5 mutations cause congenital disorder of glycosylation 2AA, manifesting as severe multisystem disease including liver dysfunction and skeletal abnormalities 2. Loss of the short isoform alone results in defective glycosylation and compromised ER-Golgi trafficking 2. STX5 function is negatively regulated by the lactate and hypoxia sensor NDRG3, which inhibits ER-to-Golgi trafficking under stress conditions 5. Additionally, elevated anti-STX5 autoantibodies serve as a potential serum biomarker for endometriosis diagnosis 6.