SMPD2 (sphingomyelin phosphodiesterase 2) is a neutral sphingomyelinase that catalyzes the hydrolysis of sphingomyelin to ceramide and phosphocholine, while also processing lyso-platelet-activating factor and lyso-phosphatidylcholine in vivo. Located at lipid raft microdomains on the plasma membrane and endoplasmic reticulum, it plays a central role in sphingolipid catabolism and ceramide biosynthesis. SMPD2 has emerged as a candidate biomarker across multiple cancer types. In hepatocellular carcinoma, SMPD2 enhanced cell survival and migration, with gene silencing increasing chemotherapy sensitivity to lapatinib 1. A pan-cancer analysis found SMPD2 expression associated with tumor stage and clinical outcomes, with methylation status inversely correlated with expression and linked to dysfunctional T cell phenotypes 2. In prostate cancer, SMPD2 inhibition by GW4869 altered the extracellular vesicle secretome and affected cell migration 3. Mechanistically, SMPD2 and ASAH1 maintain sphingolipid balance to enable lipid raft-dependent budding of polyploid giant cancer cells; disrupting these structures with statins or anti-PCSK9 antibodies enhanced radiotherapy response 4. Beyond cancer, SMPD2 upregulation was associated with improved skin barrier function and anti-aging effects in cell studies 5, while its hypermethylation was linked to suicidal ideation in schizophrenia 6. Structural studies clarified SMPD2's catalytic mechanism for sphingomyelin and lyso-PAF hydrolysis 7.