Identification of Cepharanthine as a Potential Therapy of Acid Sphingomyelinase Deficiency by Reducing Cellular Sphingosylphosphorylcholine

ABSTRACT Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by loss‐of‐function variants in the sphingomyelin phosphodiesterase‐1 ( SMPD1 ) gene encoding for the acid sphingomyelinase (ASM). Aberrantly high levels of sphingosylphosphorylcholine (SPC), the deacylated form of sphingomyelin which is the primary accumulated lipid, are key biomarkers in ASMD. The identification of small molecules targeting SPC is an attractive approach for treating ASMD. We screened 1813 Food and Drug Administration‐approved compounds to identify promising candidates that reduce SPC for treating ASMD, using a liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) assay. Eight compounds, floxuridine, dexamethasone, indacaterol maleate, triethylenethiophosphoramide, cytarabine, doramectin, cepharanthine (CEP), and tetrandrine (TE), were identified to abate the accumulation of SPC in ASMD cells. CEP and TE were selected for further pharmacological studies because of their ability to confer the greatest reduction effect on SPC. Finally, a reduction of SPC storage was verified in ASMD lymphoblasts, SMPD1‐ KO cells and SMPD1 Y496H fibroblasts by CEP treatment. Additionally, CEP could improve mitochondrial morphology and function, and stimulated lysosome biogenesis by promoting TFEB nuclear translocation in ASMD cells. These results suggest that CEP could potentially be developed as a promising candidate for treating ASMD.