SMPD2 (sphingomyelin phosphodiesterase 2) is a neutral sphingomyelinase that catalyzes the hydrolysis of sphingomyelin to generate ceramide and phosphocholine 1. The enzyme also acts on alternative substrates including lyso-platelet-activating factor, lyso-phosphatidylcholine, and sphingosylphosphocholine 12. Structurally, SMPD2 forms dimers through C-terminal transmembrane helices, with the D111-K116 loop domain essential for substrate hydrolysis 3. In cancer biology, SMPD2 plays multifaceted roles in disease progression. Pan-cancer analysis demonstrates that SMPD2 expression correlates with tumor stage and clinical outcomes, with elevated expression associated with tumor immune evasion and dysfunctional T cell phenotypes 4. SMPD2 methylation status inversely correlates with mRNA expression and predicts immunotherapy response, showing superior predictive capacity for overall survival compared to established biomarkers 4. In hepatocellular carcinoma, SMPD2 enhances cell survival and migration, with silencing increasing sensitivity to lapatinib 5. Additionally, SMPD2 maintains sphingolipid metabolic balance in radiation-induced polyploid giant cancer cells, with lipid raft disruption impairing tumor repopulation and enhancing radiosensitivity 6. Beyond cancer, SMPD2 expression is upregulated by D-alanine in skin protection studies, enhancing skin barrier function and antioxidant defense 7. Hypermethylation of SMPD2 is associated with suicidal ideation in schizophrenia, suggesting epigenetic involvement in psychiatric disease 8.