biostudies-literatureTsai YTNCI NIH HHSNIGMS NIH HHS45-58.e8https://www.ebi.ac.uk/biostudies/studies/S-EPMC12818558biostudies-literatureUnknown33(1)1-Deoxysphingolipids are non-canonical sphingolipids linked to several diseases, yet their cellular effects are poorly understood. Here, we utilize lipid chemical biology approaches to investigate the role of 1-deoxysphingolipid metabolism on the properties and functions of secretory membranes. We applied organelle-specific bioorthogonal labeling to visualize the subcellular distribution of metabolically tagged sphingolipids. We observed that 1-deoxysphingolipids are retained in the endoplasmic reticulum (ER) and specifically in ER exit sites (ERESs), suggesting that they do not efficiently sort into vesicular carriers. Cell lines expressing disease-associated variants of serine palmitoyl-CoA transferase accumulated 1-deoxysphingolipids, which were accompanied by a reduction in ER membraneCell chemical biology1-deoxysphingolipids dysregulate membrane properties and cargo trafficking in the early secretory pathway.PMC12818558R35 GM133565T32 GM139795R01 CA234245R35 GM142960T32 GM146648R35 GM141939McGregor GHNeal SLaguerre AMetallo CMBudin IKuerschner LSolorio-Kirpichyan KBrea RJSeidel ODevaraj NKVarma RTsai YTCordes TWong AMLipp NFfalse1-deoxysphingolipids dysregulate membrane properties and cargo trafficking in the early secretory pathway.1-Deoxysphingolipids are non-canonical sphingolipids linked to several diseases, yet their cellular effects are poorly understood. Here, we utilize lipid chemical biology approaches to investigate the role of 1-deoxysphingolipid metabolism on the properties and functions of secretory membranes. We applied organelle-specific bioorthogonal labeling to visualize the subcellular distribution of metabolically tagged sphingolipids. We observed that 1-deoxysphingolipids are retained in the endoplasmic reticulum (ER) and specifically in ER exit sites (ERESs), suggesting that they do not efficiently sort into vesicular carriers. Cell lines expressing disease-associated variants of serine palmitoyl-CoA transferase accumulated 1-deoxysphingolipids, which were accompanied by a reduction in ER membrane2026-01-01T00:00:00Z2026 Jan2026-06-06T19:32:50.076Z2026-06-04T03:11:57.17ZS-EPMC128185584154461610.1016/j.chembiol.2025.12.006