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Sphingolipid Metabolism and Signaling: Role in Health and Diseases—2nd Edition
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Sphingolipid Metabolism and Signaling: Role in Health and Diseases—2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (20 June 2025) | Viewed by 11737

Special Issue Editor

Dr. Paola Giussani

E-Mail Website
Guest Editor
Department of Medical Biotechnology and Translational Medicine, University of Milan, 20090 Segrate, Italy
Interests: sphingolipids; sphingosine-1-phosphate; ceramide; signaling; cancer; multiple sclerosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Sphingolipids are a class of lipids that are highly expressed in eukaryotic cells. Sphingolipids are ubiquitous components of cell membranes as well as bioactive molecules involved in the control of cell fate in physiological and pathophysiological processes. Sphingolipid metabolism and signaling are crucial for the maintenance of physiological conditions, but, on the other hand, the dysregulation of sphingolipid metabolism, leading to altered sphingolipid patterns, is associated with different pathological conditions. Sphingolipid levels are regulated via the modulation of the metabolism of specific enzymes as well as that of the specific receptors or transporters involved in their transport within or outside cells; however, the exact molecular mechanisms mediated by sphingolipids with which to modulate cell homeostasis are still not completely understood. New knowledge on the metabolism and signaling of sphingolipids will help in finding therapeutic solutions in a variety of human diseases.

For this Special Issue, “Sphingolipid Metabolism and Signaling: Role in Health and Diseases—2nd Edition”, we welcome your contributions in the form of original research and review articles on all aspects of sphingolipids and their roles in physiological and pathophysiological processes.

Dr. Paola Giussani
Guest Editor

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Keywords

  • sphingolipids
  • sphingosine-1-phosphate
  • ceramide
  • glycosphingolipids
  • sphingolipid-mediated signaling
  • cancer
  • neurodegenerative diseases
  • inflammatory diseases
  • diabetes

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Published Papers (6 papers)

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Research

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14 pages, 6164 KB  
Communication
The SGLT2 Inhibitor Dapagliflozin Disrupts the Cell Cycle at High Concentrations Without Altering Glycosphingolipid (De Novo)Biosynthesis
by Richard Jennemann and Roger Sandhoff
Int. J. Mol. Sci. 2025, 26(19), 9811; https://doi.org/10.3390/ijms26199811 - 9 Oct 2025
Viewed by 935
Abstract
Modern computational screening methods are valuable tools for repurposing approved drugs for novel therapeutic applications. They provide initial insights into alternative uses and may significantly shorten the lengthy process of drug development and regulatory approval. Treatment options for glycosphingolipidoses, lysosomal storage diseases involving [...] Read more.
Modern computational screening methods are valuable tools for repurposing approved drugs for novel therapeutic applications. They provide initial insights into alternative uses and may significantly shorten the lengthy process of drug development and regulatory approval. Treatment options for glycosphingolipidoses, lysosomal storage diseases involving glycosphingolipids (GSLs), are currently limited to a few drugs that inhibit de novo GSL biosynthesis, such as eliglustat and miglustat (Zavesca®). In the search for alternative drugs, dapagliflozin emerged as a promising candidate for off-target therapy. In the present study, we investigated whether dapagliflozin can indeed inhibit GSL synthesis, as predicted by previous computational analyses, and compared its effects with those of the glycosphingolipid synthesis inhibitor, the eliglustat analog Genz-123346, in murine 3T3 and Hepa 1-6 cell lines. While Genz-123346 significantly inhibited glycosphingolipid biosynthesis at concentrations as low as 1 µM, dapagliflozin, even up to 50 µM, had no effect on biosynthesis or de novo biosynthesis in either cell line. These results indicate that dapagliflozin, although assessing effects on the cell cycle, including proliferation at high concentrations, is not a suitable candidate for treating glycosphingolipid storage diseases by substrate reduction. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases—2nd Edition)
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16 pages, 1058 KB  
Article
Differential Effects of Sphingolipids on Cell Death and Antioxidant Defenses in Type 1 and Type 2 Endometrial Cancer Cells
by Agnieszka U. Błachnio-Zabielska, Patrycja Sadowska, Urszula Chlabicz, Karolina Pogodzińska, Hervé Le Stunff, Piotr Laudański, Jacek Szamatowicz and Mariusz Kuźmicki
Int. J. Mol. Sci. 2025, 26(10), 4472; https://doi.org/10.3390/ijms26104472 - 8 May 2025
Cited by 1 | Viewed by 1359
Abstract
Endometrial cancer (EC) is classified into two main subtypes with distinct molecular profiles. Sphingolipids, particularly ceramide and sphingosine-1-phosphate (S1P), are crucial regulators of cell survival, apoptosis, and oxidative stress. This study examined the impact of sphingolipid metabolism in Ishikawa (type 1) and HEC-1A [...] Read more.
Endometrial cancer (EC) is classified into two main subtypes with distinct molecular profiles. Sphingolipids, particularly ceramide and sphingosine-1-phosphate (S1P), are crucial regulators of cell survival, apoptosis, and oxidative stress. This study examined the impact of sphingolipid metabolism in Ishikawa (type 1) and HEC-1A (type 2) EC cells following the silencing of Sptlc1 and Sptlc2, which encode subunits of serine palmitoyltransferase (SPT), a key enzyme in de novo sphingolipid synthesis. Gene silencing was confirmed by RT-PCR and Western blot, while sphingolipid levels were quantified using UHPLC/MS/MS and the sphingolipid rheostat (S1P/ceramide ratio) was calculated. Cell viability (MTT assay), cell death, ROS levels (ELISA), total antioxidant capacity (TAC), catalase and caspase-3 activity, and mitochondrial membrane potential were also assessed. The obtained data showed higher ceramide levels in Ishikawa(CON) cells and higher S1P levels in HEC-1A(CON) cells, resulting in a higher sphingolipid rheostat in HEC-1A cells. SPT knockdown reduced sphingolipid levels, increased cell viability, elevated ROS levels, and decreased cell death, particularly in Ishikawa cells. Furthermore, after gene silencing, these cells exhibited reduced catalase activity and diminished TAC, indicating an impaired redox balance. These findings reveal subtype-specific responses to disrupted sphingolipid synthesis and highlight the importance of sphingolipid homeostasis in the behavior of EC cells. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases—2nd Edition)
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11 pages, 1305 KB  
Article
Untargeted Urinary Volatilomics Reveals Hexadecanal as a Potential Biomarker for Preeclampsia
by Marina Pehlić, Stipe Dumančić, Mila Radan, Jelena Galić, Branimir Gruica, Sandra Marijan and Marko Vulić
Int. J. Mol. Sci. 2024, 25(22), 12371; https://doi.org/10.3390/ijms252212371 - 18 Nov 2024
Cited by 2 | Viewed by 1752
Abstract
Preeclampsia (PE) is a severe hypertensive pregnancy disorder characterized by endothelial dysfunction, placental ischemia and oxidative stress; however, reliable non-invasive biomarkers for early detection are limited. In this study, untargeted solid-phase microextraction with gas chromatography–mass spectrometry (SPME-GC-MS) was used to analyze volatile organic [...] Read more.
Preeclampsia (PE) is a severe hypertensive pregnancy disorder characterized by endothelial dysfunction, placental ischemia and oxidative stress; however, reliable non-invasive biomarkers for early detection are limited. In this study, untargeted solid-phase microextraction with gas chromatography–mass spectrometry (SPME-GC-MS) was used to analyze volatile organic compounds in the urine of 45 women with PE and 46 healthy controls. Among the 29 metabolites identified, hexadecanal—a product of lipid peroxidation and sphingolipid metabolism—was found to be the most significant, with an area under the receiver operating characteristic (ROC) curve of 0.618, highlighting its diagnostic potential. This result emphasizes the role of hexadecanal in oxidative stress and placental dysfunction, which are central to the pathophysiology of PE. The results support hexadecanal as a potential non-invasive biomarker while demonstrating the efficacy of SPME-GC-MS in identifying metabolic disorders associated with PE, paving the way for further research to confirm its clinical utility for early diagnosis and risk assessment. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases—2nd Edition)
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15 pages, 2245 KB  
Article
Monitoring Myelin Lipid Composition and the Structure of Myelinated Fibers Reveals a Maturation Delay in CMT1A
by Giovanna Capodivento, Mattia Camera, Nara Liessi, Anna Trada, Doriana Debellis, Angelo Schenone, Andrea Armirotti, Davide Visigalli and Lucilla Nobbio
Int. J. Mol. Sci. 2024, 25(20), 11244; https://doi.org/10.3390/ijms252011244 - 19 Oct 2024
Cited by 3 | Viewed by 2565
Abstract
Findings accumulated over time show that neurophysiological, neuropathological, and molecular alterations are present in CMT1A and support the dysmyelinating rather than demyelinating nature of this neuropathy. Moreover, uniform slowing of nerve conduction velocity is already manifest in CMT1A children and does not improve [...] Read more.
Findings accumulated over time show that neurophysiological, neuropathological, and molecular alterations are present in CMT1A and support the dysmyelinating rather than demyelinating nature of this neuropathy. Moreover, uniform slowing of nerve conduction velocity is already manifest in CMT1A children and does not improve throughout their life. This evidence and our previous studies displaying aberrant myelin composition and structure in adult CMT1A rats prompt us to hypothesize a myelin and axon developmental defect in the CMT1A peripheral nervous system. Peripheral myelination begins during the early stages of development in mammals and, during this process, chemical and structural features of myelinated fibers (MFs) evolve towards a mature phenotype; deficiencies within this self-modulating circuit can cause its blockage. Therefore, to shed light on pathophysiological mechanisms that occur during development, and to investigate the relationship among axonal, myelin, and lipidome deficiencies in CMT1A, we extensively analyzed the evolution of both myelin lipid profile and MF structure in WT and CMT1A rats. Lipidomic analysis revealed a delayed maturation of CMT1A myelin already detectable at P10 characterized by a deprivation of sphingolipid species such as hexosylceramides and long-chain sphingomyelins, whose concentration physiologically increases in WT, and an increase in lipids typical of unspecialized plasma membranes, including phosphatidylcholines and phosphatidylethanolamines. Consistently, advanced morphometric analysis on more than 130,000 MFs revealed a delay in the evolution of CMT1A axon and myelin geometric parameters, appearing concomitantly with lipid impairment. We here demonstrate that, during normal development, MFs undergo a continuous maturation process in both chemical composition and physical structure, but these processes are delayed in CMT1A. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases—2nd Edition)
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Review

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17 pages, 1132 KB  
Review
Sphingosine-1-Phosphate Metabolic Pathway in Cancer: Implications for Therapeutic Targets
by Miguel L. Rufail, Rosaria Bassi and Paola Giussani
Int. J. Mol. Sci. 2025, 26(3), 1056; https://doi.org/10.3390/ijms26031056 - 26 Jan 2025
Cited by 8 | Viewed by 3618
Abstract
Cancer biology revolves around understanding how cells undergo uncontrolled proliferation leading to the formation of malignant tumors. Key aspects include self-sufficiency in growth signals, the lack of response to signals of growth inhibition, the evasion of apoptosis, sustained angiogenesis, the evasion of immune [...] Read more.
Cancer biology revolves around understanding how cells undergo uncontrolled proliferation leading to the formation of malignant tumors. Key aspects include self-sufficiency in growth signals, the lack of response to signals of growth inhibition, the evasion of apoptosis, sustained angiogenesis, the evasion of immune response, the capacity to invade and metastasize, and alterations in cellular metabolism. A vast amount of research, which is exponentially growing, over the past few decades highlights the role of sphingolipids in cancer. They act not only as structural membrane components but also as bioactive molecules that regulate cell fate in different physio-pathological conditions. In cancer, sphingolipid metabolism is dysregulated, contributing to tumor progression, metastasis, and drug resistance. In this review, we outline the impact of sphingosine-1-phosphate (S1P) as a key bioactive sphingolipid in cancer. We give an overview of its metabolism summarizing the role of S1P as an intracellular and extracellular mediator through specific plasma membrane receptors in different cancers. We also describe previous findings on how the disruption in the balance between S1P and ceramide (Cer) is common in cancer cells and can contribute to tumorigenesis and resistance to chemotherapy. We finally consider the potential of targeting the metabolic pathways of S1P as well as its receptors and transporters as a promising therapeutic approach in cancer treatments. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases—2nd Edition)
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Other

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14 pages, 1796 KB  
Brief Report
Lipid Signature of Motile Human Sperm: Characterization of Sphingomyelin, Ceramide, and Phospholipids with a Focus on Very Long Chain Polyunsaturated Fatty Acids
by Gerardo Martín Oresti, Jessica Mariela Luquez and Silvia Alejandra Belmonte
Int. J. Mol. Sci. 2025, 26(19), 9301; https://doi.org/10.3390/ijms26199301 - 23 Sep 2025
Viewed by 786
Abstract
Sperm membrane lipids play a crucial role in male fertility, influencing sperm motility, viability, and functional competence. This study comprehensively characterizes the phospholipid and sphingolipid composition in highly motile human spermatozoa obtained through the swim-up method, a widely used technique in assisted reproductive [...] Read more.
Sperm membrane lipids play a crucial role in male fertility, influencing sperm motility, viability, and functional competence. This study comprehensively characterizes the phospholipid and sphingolipid composition in highly motile human spermatozoa obtained through the swim-up method, a widely used technique in assisted reproductive technology (ART). Using two-dimensional thin-layer chromatography and phosphorus analysis, we identified choline glycerophospholipids (CGP, 45%), ethanolamine glycerophospholipids (EGP, 26%), and sphingomyelin (SM, 17%) as predominant phospholipids, with minor components including cardiolipin, lysophospholipids, phosphatidylinositol, phosphatidylserine, phosphatidic acid, and neutral lipids. Gas chromatography analysis of glycerophospholipids (GPL) revealed a high long chain (C20–C22) polyunsaturated fatty acids (PUFA) content (46.3%), particularly docosahexaenoic acid (DHA, 22:6n-3), which was more abundant in CGP (46%) than EGP (26%). Sphingolipid analysis indicated that ceramide (Cer) and SM shared similar fatty acid profiles due to their metabolic relationship, with very-long-chain (VLC) PUFA (≥C26) being more prevalent in SM (10%) than in Cer (6%). Additionally, argentation chromatography identified highly unsaturated VLCPUFA species in Cer, including 28:3n-6, 28:4n-6, and 30:4n-6, which had not been previously quantified in motile human spermatozoa. Given the essential function of sphingolipid metabolism in spermatogenesis, capacitation, and acrosomal exocytosis, our findings suggest that the balance of VLCPUFA-containing SM and Cer could play a role in sperm performance and fertilization potential. This study provides novel insights into the lipid signature of human sperm and highlights the relevance of membrane lipid remodeling for male fertility and ART outcomes. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases—2nd Edition)
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