Acid sphingomyelinase (ASM), encoded by SMPD1, regulates sphingolipid metabolism and has been implicated in tumor progression and immune modulation. However, its role in glioma remains poorly defined. We performed a comprehensive analysis of SMPD1 in gliomas using TCGA and CGGA datasets, evaluating its expression patterns, prognostic significance, immune correlations, pathway enrichment, and copy number variation. Using qRT-PCR, we validated invitro the effect of SMPD1 expression on macrophage polarization. Immunofluorescence staining was used to assess the levels of ASM of clinical samples and its correlation with tumor-associated macrophages. The functional role of SMPD1 was further validated invivo. SMPD1 expression was significantly elevated in high-grade, IDH-wildtype, and MGMT-unmethylated gliomas. High SMPD1 levels were associated with poor prognosis and served as an independent prognostic factor. Tumors with elevated SMPD1 showed increased infiltration of regulatory T cells and M0/M2 macrophages. SMPD1 expression correlated with multiple immune cell markers and immune checkpoint molecules. Cell-based experiments showed that knocking out or inhibiting ASM drives macrophages toward an M1 phenotype while suppressing M2 polarization. Immunofluorescence analysis confirmed upregulation of ASM protein in high-grade, IDH-wildtype gliomas, with a strong positive correlation with CD163 expression in clinical samples. Invivo, inhibition of SMPD1 significantly suppressed glioma growth. SMPD1 is a potential biomarker and therapeutic target in gliomas. Its upregulation may contribute to the formation of an immunosuppressive microenvironment and promote tumor progression, highlighting its potential relevance in glioma immunotherapy.

Olipudase alfa treatment for pediatric acid sphingomyelinase deficiency in Egypt: A prospective, observational cohort study with an interventional subgroup.

Stargardt disease, which destroys central high-resolution vision in over 2 million people globally, lacks effective therapies. The primary site of damage in Stargardt disease is the retinal pigment epithelium (RPE), which safeguards photoreceptor health and function. Progressive loss of RPE integrity precedes visual deficits, yet insight into mechanisms driving RPE dysfunction and how this influences disease pathogenesis remains elusive. Here, we addressed this in cell-based and pigmented Abca4−/− Stargardt mice models using super-resolution imaging, bioinformatics, and biochemical approaches. We show that ceramide accumulation induced by bisretinoid-mediated overactivation of acid sphingomyelinase (ASM) in Abca4−/− RPE selectively disrupts Rab GTPases and ESCRT machinery involved in apical membrane trafficking and small extracellular vesicle (EV) biogenesis. Consequently, connexin 43 (Cx43) is misrouted from cell-cell junctions into EVs that are released apically by the RPE. This compromises RPE integrity and promotes subretinal immune cell recruitment, leading to photoreceptor dysfunction. Pharmacological ASM inhibition normalizes EV biogenesis and restores Cx43 localization. Decreasing RPE ceramide safeguards RPE structural integrity, limits subretinal microglia, and improves visual function in Abca4−/− mice. This study underscores the importance of the RPE as a communication hub in the retina and identifies ASM as a potential therapeutic target to prevent progressive vision loss.

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogenous clinical manifestations, including interstitial lung disease (ILD). Respiratory manifestations are the leading causes of mortality in patients with ASMD type B and typeA/B. In ILD, the percent predicted diffusing capacity of the lungs for carbon monoxide (DLCO) is a common clinical endpoint; however, its clinical relevance in patients with ASMD remains unclear. This post hoc analysis explored the relationship between DLCO and mortality risk in patients with ASMD type B and type A/B. Data from a prospective natural history study (NCT02004704) and a retrospective cohort study conducted in the United States were pooled based on the eligibility criteria. Percent predicted DLCO was imputed for 10 records (9/68 patients), assuming an annual 1% linear decrease in DLCO. A Cox proportional hazards model was fitted using percent predicted DLCO as a time-varying predictor at < 60% and ≥ 60%. A total of 68 patients (prospective study, n = 40; retrospective study, n = 28) diagnosed with ASMD type B or typeA/B during childhood (aged 1-12years) with ≥ 1 DLCO measurement were included in the analysis. A total of 12 deaths were recorded. The estimated hazard ratio (95% confidence interval) was 0.77 (0.22-2.67), indicating a potential trend toward an association of lower mortality risk with higher percent predicted DLCO (≥ 60%). However, the result was not statistically significant (p = 0.69) because of the limited sample size, thus warranting further prospective validation. To our knowledge, this is the first analysis to explore the relationship between DLCO and mortality risk in patients with ASMD type B andtype A/B. Overall, these findings underscore how DLCO affects the mortality risk in patients with ASMD.

From childhood to adulthood: A descriptive analysis of clinical features in patients with acid sphingomyelinase deficiency (ASMD)

Anti-transferrin receptor 1-targeted AAV9 therapy prevents CNS and visceral pathologies in acid sphingomyelinase deficiency

ABSTRACTBackgroundAcid sphingomyelinase deficiency (ASMD) is a rare lysosomal disorder with diverse clinical presentations and often delayed diagnosis. This study investigates the clinical features, genetic variants, and treatment outcomes in Taiwanese patients.MethodsWe retrospectively reviewed nine ASMD cases in Taiwan, including genetic data and responses to olipudase alfa. Newborn screening data using the NeoLSD MS/MS kit for dried blood spot enzyme activity, followed by lyso‐sphingomyelin and molecular testing, were also analysed.ResultsThe SMPD1 c.1497_1498inv variant was found in 62.5% of alleles among chronic neurovisceral ASMD cases, while c.995C > G appeared in 37.5% of chronic visceral ASMD cases and was also frequent in partial ASMD from newborn screening. Four patients received olipudase alfa; Patient 1, treated for 3 years starting at age 41, showed improved pulmonary function despite persistent thrombocytopenia and splenomegaly. Patients 2, 6, and 7, treated from early childhood, exhibited marked improvements in hepatosplenomegaly, interstitial lung disease, and growth within 1 year of therapy.ConclusionThis study highlights distinct genotype–phenotype correlations in ASMD and supports the clinical benefits of olipudase alfa. Increased awareness and early diagnosis, potentially through newborn screening, are essential for optimizing outcomes in ASMD.

Leukocyte acid sphingomyelinase analysis in control population and patients with clinical suspicion of Niemann-Pick disease type A/B

Haemorrhagic stroke in an adult patient affected with acid sphingomyelinase deficiency

Demyelinating diseases are heterogeneous in their etiology, clinical course, and manifestations. In the long run, however, they lead to irreversible dysfunction of the nervous system. Although myelin regeneration occurs in response to myelin damage in both animal models of demyelination and human patients, the outcome is usually less favorable in humans. This explains the interest in treatments that could improve the effectiveness of myelin regeneration. Among these, treatment with the monoclonal antibody rHIgM22 has been shown to effectively enhance myelin regeneration in both immune and non-immune mouse models of demyelination. Its administration to patients with multiple sclerosis was well tolerated, and it was detected in the cerebrospinal fluid, suggesting penetration of the central nervous system. Previously, we demonstrated that administering rHIgM22 to rat mixed glial cultures alters the balance between ceramide and sphingosine 1-phosphate (S1P), thereby inducing S1P release and astrocyte and oligodendrocyte precursor cell (OPC) proliferation. In this paper, we studied the effects of rHIgM22 treatment on the lipid composition of purified glial cultures from the rat brain, including astrocytes, OPC, and oligodendrocytes (OL) at various stages of in vitro differentiation. rHIgM22 did not affect the phospholipid composition of any of the analyzed cell types. A steady-state metabolic labeling procedure revealed that sphingolipid patterns were unaffected by rHIgM22 treatment in astrocytes. However, rHIgM22 treatment significantly increased the levels of GM3 and GD3 gangliosides in oligodendroglial cells. The increase in GM3 and GD3 versus controls was highest in fully differentiated OL. We also detected a slight but significant reduction in cholesterol levels and in vitro acid sphingomyelinase activity in these cells. Acid sphingomyelinase is a key enzyme in sphingolipid metabolism. Thus, the effect of rHIgM22 on lipid metabolism is cell-specific among different glial populations. We hypothesize that the myelin regeneration effects of rHIgM22 could result from alterations in lipid-dependent membrane organization in oligodendroglial cells.

Metabolomic changes related to colorectal cancer (CRC) may serve as diagnostic markers to identify patients may develop or have developed CRC. Untargeted lipidomics were performed on serum from CRC cases and clean-colon controls from the Chicago Colorectal Cancer Consortium (CCCC) and the University of Arizona Cancer Center (UACC). Untargeted lipidomics in the CCCC CRC series revealed significant alterations in sphingolipids. Targeted lipidomics revealed a signature of five sphingomyelins (SMs) were significantly decreased in CRC patients in CCCC and UACC CRC series. Circulating SMs are degraded primarily by S-SMase and serum S-SMase activity was significantly higher in UACC cases as compared to controls. Serum S-SMase activity was also measured in two series of adenoma patients to determine if S-SMase may serve as a biomarker for development of colorectal neoplasia. While S-SMase activity was significantly higher in adenoma patients compared to controls in the mostly white UACC series, S-SMase activity in samples from the Chicago Black series (CCCC) were indistinguishable from each other and significantly higher than UACC controls. Together, these studies suggest the potential for S-SMase activity to serve as a biomarker for colorectal neoplasia, with potential implications in some but perhaps not all populations.

Niemann-Pick disease is a rare genetic disorder with an autosomal recessive inheritance pattern, which belongs to a group of sphingolipid metabolism diseases. According to available data, Niemann-Pick disease type B is caused by mutations in the SMPD1 gene, which is located on the short arm of chromosome 11. A missense substitution leads to insufficient production of the lysosomal enzyme acid sphingomyelinase, which is responsible for the breakdown of sphingomyelin. As a result, sphingomyelin accumulates in the cells of the reticuloendothelial system, leading to abnormalities in various organs. This article describes a clinical case of an adolescent girl with Niemann-Pick disease type B, in whom typical changes in the internal organs were identified using several medical imaging modalities.

Background: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive lysosomal storage disease with heterogeneous clinical manifestations. Evidence on the disease burden of ASMD is limited in Brazil. Methods: This observational, multicenter, retrospective study assessed the characteristics and clinical data of patients with ASMD type B and type A/B. Patients' demographic data were retrieved from Hospital de Clínicas de Porto Alegre between January 1, 1986 and May 31, 2021, and available medical records were collected from eight centers in Brazil. Results: The study included 124 patients (full cohort: ASMD type B [75.8%] and type A/B [24.2%]; median [interquartile range {IQR}] age: 10.0 [3.6-19.9] years at diagnosis, n = 94), while medical records were available for 24 patients (subset cohort: ASMD type B [87.5%] and type A/B [12.5%]; median [IQR] age: 6.7 [1.9-11.3] years at diagnosis). Hepatobiliary and splenic manifestations were the most common clinical findings at symptom onset/diagnosis (75.0% and 70.8%, respectively) and at the last follow-up/death (83.3% each), with the majority of patients showing abnormal liver function parameters at both time points. At least 50.0% of patients had comorbidities at symptom onset or diagnosis. The incidence of hospitalization was reported in 33.3% patients at symptom onset/diagnosis and in 45.9% at the last follow-up/death. During the follow-up period, two patients with ASMD type A/B died in the subset cohort. Conclusions: The study provides insights into the high burden of illness in patients with ASMD, highlighting the need for disease awareness and early diagnosis in Brazil.

Metabolic improvement in patients with acid sphingomyelinase deficiency following intravenous trehalose administration: an untargeted pharmacometabolomic study.

Tauopathies are neurodegenerative diseases characterized by accumulation of hyperphosphorylated tau protein (P-tau). The gut microbiota (GM) is symbiotic with the host and altered in neurodegenerative diseases. Amitriptyline (AMI) is a functional inhibitor of acid sphingomyelinase (ASM) which is abnormally highly expressed in brains of Alzheimer patients. Little data is known about the role of colonic ASM in management of tauopathy. Therefore, the aim of this study was to investigate the role of AMI on reversing gut dysbiosis, ceramide levels, colonic inflammation and intestinal barrier disruption in tauopathy through the bidirectional gut-brain axis. P301S transgenic mice were administered AMI for 35 days. Colonic ASM, ceramides, inflammation and membrane integrity were assessed besides fecal microbiome analysis and serum lipopolysaccharides to assess intestinal membrane disruption. Levels of hippocampal P-tau, protein phosphatase 2 A and neurogenesis were assessed along with cognitive behavior. AMI treatment significantly reduced colonic ASM, ceramide levels, increased abundance of Harryflintia, Dubosiella, and Parasutterella and decreased abundance of Lactobacillus, Lachnoclostridium, Oscillibacter, Oscillospiracea UCG-003, Colidextribacter, Roseburia, Butyricicoccus, and Sphingomondales. In contrast, P301S mice displayed an altered GM profile with enriched Firmicutes and Clostridia, and low proportions of Bacteroidota- a phylum associated with intestinal barrier protection-, and Ruminococcaceae. Also, AMI treatment decreased inflammation and restored colonic membrane integrity with subsequent decrease in serum lipopolysaccharides, P-tau in hippocampus and improvement in cognitive behaviour and neurogenesis. The current results indicate that AMI has neuroprotective effects against tauopathy through modulation of ASM activity, associated ceramide levels, GM composition, colonic inflammation and membrane integrity through bidirectional gut-brain axis.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1007/s11481-025-10270-x.

Background: Gaucher disease (GD) and Acid Sphingomyelinase Deficiency (ASMD) are rare, chronic, function progressive, and debilitating disorders caused by the altered lysosomal enzymes glucocerebrosidase (GCase) in GD and sphingomyelinase (ASM) in ASMD respectively. These pathologies share several clinical manifestations, and their real incidence is underestimated.

New multiplex LC-MS/MS method for lipid biomarker analysis of inherited neurodegenerative metabolic diseases.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype with poor prognosis and limited treatment options, largely due to the presence of breast cancer stem cells (BCSCs) that contribute to chemotherapy resistance, metastasis, and relapse. In this study, we investigated the therapeutic potential of polysaccharides from Huaier (PS-T) in targeting BCSCs via a novel mechanism involving autophagy-dependent ferroptosis. We first identified a 17-gene stemness signature from TCGA data of 167 TNBC patients, which correlated with poor prognosis. Using this signature, we developed a prognostic model that demonstrated strong predictive power for TNBC survival. In vitro, PS-T treatment significantly reduced the stemness markers POU5F1, SOX2, and NANOG, and decreased the ALDH+ and CD44highCD24low BCSC populations in a dose-dependent manner. PS-T also suppressed colony formation and mammosphere growth in ALDH+ TNBC cells. Ferroptosis induction was confirmed by increased intracellular reactive oxygen species (ROS) and lipid peroxidation, with these effects reversed by ferroptosis inhibitors. Mechanistically, PS-T downregulated GPX4, a key regulator of ferroptosis, through an autophagy-dependent pathway. This process was further enhanced by PS-T-induced upregulation of acid sphingomyelinase (ASM), which facilitated autophagic degradation of GPX4. In vivo, PS-T treatment significantly reduced tumor formation from ALDH+ TNBC cells. Overall, our findings suggest that PS-T inhibits BCSC stemness and promotes ferroptosis, providing a promising therapeutic strategy for improving the prognosis of TNBC patients.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s12935-025-04102-4.

Besides its robust antiviral activity, type I interferon (IFN-I) also exerts immunomodulatory effects and can even drive pathology during chronic viral infections. Mechanisms that regulate IFN-I induction during virus infection, thus strongly affecting the outcome of disease, remain to be defined. Here, using the lymphocytic choriomeningitis virus (LCMV) Docile strain, we identified acid ceramidase (aCDase, Asah1) as a critical lipid-metabolic regulator of endosomal, nucleic acid-driven IFN-I responses and disease outcome during chronic virus infection. aCDase is highly expressed in plasmacytoid dendritic cells (pDCs) and required for robust early IFN-I production. aCDase deficiency resulted in ceramide accumulation, blunting IFN-α/β induction, impairing IFN-I-dependent upregulation of programmed death-ligand 1 (PD-L1) on antigen-presenting cells and preventing the exhaustion of virus-specific CD8+ T cells, leading to severe immunopathology. This pathology is abrogated by CD8+ T-cell depletion or by adoptive transfer of IFN-I-induced PD-L1-expressing macrophages. Conversely, limiting ceramide production in acid sphingomyelinase (Asm)-deficient mice prevented ceramide accumulation, and pDCs showed accelerated IFN-I induction. Mechanistically, ceramide abundance regulated IFN-I production by altering endosomal signaling microdomains. Collectively, our findings reveal ceramide homeostasis as a key determinant of IFN-I-driven CD8+ T-cell exhaustion and immunopathology during chronic viral infection and highlight aCDase as a potential therapeutic target.

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 SMPD1Y496H 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.