SPTSSB is a regulatory subunit of the serine palmitoyltransferase (SPT) complex, which catalyzes the rate-limiting step of de novo sphingolipid biosynthesis by condensing L-serine with activated acyl-CoA to form long-chain bases. Within the SPT heterotrimer, SPTSSB stimulates catalytic activity and controls substrate specificity; notably, the SPTLC1-SPTLC2-SPTSSB complex preferentially utilizes C18-CoA substrates, while SPTLC1-SPTLC3-SPTSSB accepts a broader acyl-CoA range. SPTSSB is prominently expressed in epithelial tissues, including urothelium and keratinocytes, where it influences long-chain base composition during differentiation. Pathogenic SPTSSB variants disrupt sphingolipid homeostasis with clinical consequences. A mutation in SPTSSB (Stellar) increased affinity for C18 substrates and elevated 20-carbon long-chain base production, causing neurodegeneration with axon degeneration and protein aggregation, demonstrating that abnormal chain-length distribution impairs neural function 1. Common SPTSSB variants are associated with elevated plasma ceramides and increased Parkinson's disease risk via altered de novo sphingolipid biosynthesis 2. SPTSSB dysregulation has been implicated in age-related macular degeneration and intervertebral disc degeneration 3. Chemoproteomics identified gambogic acid and related xanthones as covalent SPTSSB inhibitors that reduce sphingolipid levels in vitro and in vivo, suggesting SPTSSB as a therapeutic target in diseases with pathological sphingosine-1-phosphate signaling 4.