SMPD3 (sphingomyelin phosphodiesterase 3) catalyzes hydrolysis of sphingomyelin to ceramide and phosphocholine, functioning as a key regulator of sphingolipid metabolism 1. This enzymatic activity controls cellular ceramide levels, which mediate critical processes including apoptosis, growth arrest, and cell cycle regulation [UniProt annotation]. SMPD3 operates within an intestinal farnesoid X receptor (FXR) signaling axis: FXR activation upregulates SMPD3 expression, increasing ceramide production and promoting disease pathology 2. In metabolic-dysfunction-associated steatohepatitis (MASH), hepatic SMPD3 becomes upregulated following lipotoxicity-induced DNA damage and SIRT1 suppression, disrupting membrane sphingolipid balance and exacerbating inflammation and fibrosis through enhanced lipid uptake and extracellular vesicle secretion 1. Similarly, in smoking-related NAFLD progression, nicotine activates intestinal AMPKα, which phosphorylates and stabilizes SMPD3, promoting ceramide formation 3. SMPD3 also contributes to inflammatory bowel disease pathogenesis via the FXR-SMPD3 axis controlling ceramide synthesis 4. Conversely, SMPD3 overexpression in bone marrow stem cells promotes osteogenic differentiation and bone regeneration under glucose fluctuation stress 5. Proteogenomic analysis associates SMPD3 dysregulation with Parkinson's disease pathogenesis 6. SMPD3 inhibition emerges as a therapeutic strategy for metabolic and inflammatory diseases.