SPTLC2 encodes a catalytic subunit of serine palmitoyltransferase (SPT), the rate-limiting enzyme in de novo sphingolipid biosynthesis 1. The enzyme catalyzes condensation of L-serine and acyl-CoA to form long-chain bases, with SPTLC1-SPTLC2 heterodimers showing strong preference for C16-CoA substrates 2. SPTLC2 expression is upregulated in hepatocytes during metabolic dysfunction-associated steatohepatitis (MASH), where it drives pathogenic ceramide accumulation 3. In brain ischemia, SPTLC2 promotes ceramide production in astrocytes, triggering mitochondrial permeabilization, mtDNA release, and neuroinflammation through cGAS/STING signaling 4. The enzyme incorporates trans-fatty acids preferentially into sphingolipids, contributing to atherosclerotic cardiovascular disease through altered lipoprotein trafficking 2. Gain-of-function mutations in SPTLC2 cause juvenile amyotrophic lateral sclerosis by disrupting SPT regulation and increasing ceramide levels 5. Therapeutically, SPTLC2 knockdown reduces ceramide synthesis and ameliorates both brain ischemic injury and MASH progression 43. The enzyme also responds to nicotinamide treatment, enhancing ceramide biosynthesis to improve epidermal barrier function 6.