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Sphingolipid Metabolism and Signaling in Health and Diseases
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Sphingolipid Metabolism and Signaling in Health and Diseases

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

Deadline for manuscript submissions: 20 July 2025 | Viewed by 11096

Special Issue Editor

Dr. Gergana M. Deevska

E-Mail Website
Guest Editor
College of Osteopathic Medicine, Sam Houston State University, Conroe, TX 77304, USA
Interests: sphingolipid metabolism and signaling; obesity; diabetes; fatty liver disease; cardiometabolic syndrome

Special Issue Information

Dear Colleagues,

We kindly invite you to contribute to this IJMS Special Issue entitled ‘Sphingolipid Metabolism and Signaling in Health and Diseases’ focused on the multifaceted aspects of sphingolipids' role in maintaining health and contributing to disease pathogenesis.

Sphingolipids, a diverse and ubiquitous group of lipids, are integral to several essential cellular functions and are implicated in various dysfunction and disease states. They are not only involved in intracellular trafficking and serve as structural components of cell membranes, providing stability and fluidity to the lipid bilayer, but also play various essential roles as secondary messengers in cell signaling pathways, regulating critical processes like cell growth, proliferation, and apoptosis. Additionally, sphingolipids are pivotal in maintaining cell integrity and barrier functions in the skin and gastrointestinal tract. Dysregulation of sphingolipid metabolism and altered signaling are implicated in various pathological conditions, including neurodegenerative disorders such as ALS, Alzheimer's, and Parkinson's, as well as cancer, diabetes, obesity, and cardiometabolic disorders. Moreover, chronic inflammation and immune system dysfunctions have been associated with sphingolipid imbalances, contributing to autoimmune diseases, chronic inflammatory states related to certain conditions, and aging.

In this Special Issue, we welcome original research articles and review articles that shed light on the underlying mechanisms, regulatory pathways, and interplay of sphingolipids in different physiological and pathological contexts, as well as submissions examining potential therapeutic interventions targeting sphingolipid signaling and metabolic pathways.

Dr. Gergana M. Deevska
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • ceramide
  • ceramide-1-phosphate
  • sphingosine
  • sphingosine-1-phosphate
  • sphingomyelin
  • glycosphingolipids
  • metabolic syndrome
  • obesity
  • diabetes
  • cancer
  • neurodegeneration
  • neuroinflammation
  • autoimmunity

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Published Papers (5 papers)

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Research

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14 pages, 2520 KiB  
Article
The Interplay between Oxidative Stress and Sphingolipid Metabolism in Endometrial Cancer
by Agnieszka U. Błachnio-Zabielska, Patrycja Sadowska, Michał Zdrodowski, Piotr Laudański, Jacek Szamatowicz and Mariusz Kuźmicki
Int. J. Mol. Sci. 2024, 25(19), 10243; https://doi.org/10.3390/ijms251910243 - 24 Sep 2024
Cited by 1 | Viewed by 1429
Abstract
Endometrial cancer is one of the most common malignancies in women. Sphingolipids, a group of lipids, play a key role in cancer biology. Cancer cells often exhibit abnormal redox homeostasis characterized by elevated levels of reactive oxygen species (ROS). Emerging evidence suggests that [...] Read more.
Endometrial cancer is one of the most common malignancies in women. Sphingolipids, a group of lipids, play a key role in cancer biology. Cancer cells often exhibit abnormal redox homeostasis characterized by elevated levels of reactive oxygen species (ROS). Emerging evidence suggests that ceramides are involved in inhibiting proliferation and inducing apoptosis through ROS production. However, there is no data on the relationship between sphingolipid metabolism and oxidative status in endometrial cancer. The present study aims to assess the content of individual sphingolipids and oxidative status in healthy women and those with endometrial cancer. Sphingolipid analysis was performed using mass spectrometry. Total oxidative status (TOS) and total antioxidant capacity (TAC) were assessed colorimetrically. Our results showed a significant increase in the levels of all measured sphingolipids in cancer tissues compared to healthy endometrium. Additionally, a significant decrease in the S1P/ceramide ratio (sphingolipid rheostat) was observed in cancer patients, particularly for C14:0-Cer, C16:0-Cer, C18:1-Cer, C22:0-Cer, and C24:0-Cer. Furthermore, increased TOS and decreased TAC were found in cancer patients compared to healthy women. Significant correlations were observed between the levels of individual sphingolipids and oxidative status, with the strongest correlation noted between C22:0-Cer and TOS (r = 0.64). We conclude that endometrial cancer is characterized by profound changes in sphingolipid metabolism, contributing to oxidative dysregulation and tumor progression. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Health and Diseases)
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13 pages, 1718 KiB  
Article
Wide-Targeted Semi-Quantitative Analysis of Acidic Glycosphingolipids in Cell Lines and Urine to Develop Potential Screening Biomarkers for Renal Cell Carcinoma
by Masamitsu Maekawa, Tomonori Sato, Chika Kanno, Izumi Sakamoto, Yoshihide Kawasaki, Akihiro Ito and Nariyasu Mano
Int. J. Mol. Sci. 2024, 25(7), 4098; https://doi.org/10.3390/ijms25074098 - 7 Apr 2024
Viewed by 1962
Abstract
Glycosphingolipids (GSLs), mainly located in the cell membrane, play various roles in cancer cell function. GSLs have potential as renal cell carcinoma (RCC) biomarkers; however, their analysis in body fluids is challenging because of the complexity of numerous glycans and ceramides. Therefore, we [...] Read more.
Glycosphingolipids (GSLs), mainly located in the cell membrane, play various roles in cancer cell function. GSLs have potential as renal cell carcinoma (RCC) biomarkers; however, their analysis in body fluids is challenging because of the complexity of numerous glycans and ceramides. Therefore, we applied wide-targeted lipidomics using liquid chromatography–tandem mass spectrometry (LC–MS/MS) with selected reaction monitoring (SRM) based on theoretical mass to perform a comprehensive measurement of GSLs and evaluate their potency as urinary biomarkers. In semi-quantitative lipidomics, 240 SRM transitions were set based on the reported/speculated structures. We verified the feasibility of measuring GSLs in cells and medium and found that disialosyl globopentaosylceramide (DSGb5 (d18:1/16:0)) increased GSL in the ACHN medium. LC–MS/MS analysis of urine samples from clear cell RCC (ccRCC) patients and healthy controls showed a significant increase in the peak intensity of urinary DSGb5 (d18:1/16:0) in the ccRCC group compared with that in the control group. Receiver operating characteristic analysis indicated that urinary DSGb5 could serve as a sensitive and specific marker for RCC screening, with an AUC of 0.89. This study demonstrated the possibility of urinary screening using DSGb5 (d18:1/16:0). In conclusion, urinary DSGb5 (d18:1/16:0) was a potential biomarker for cancer screening, which could contribute to the treatment of RCC patients. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Health and Diseases)
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15 pages, 2538 KiB  
Article
The Sphingolipid-Modulating Drug Opaganib Protects against Radiation-Induced Lung Inflammation and Fibrosis: Potential Uses as a Medical Countermeasure and in Cancer Radiotherapy
by Lynn W. Maines, Staci N. Keller, Ryan A. Smith, Cecelia L. Green and Charles D. Smith
Int. J. Mol. Sci. 2024, 25(4), 2322; https://doi.org/10.3390/ijms25042322 - 15 Feb 2024
Cited by 1 | Viewed by 2633
Abstract
Fibrosis is a chronic pathology resulting from excessive deposition of extracellular matrix components that leads to the loss of tissue function. Pulmonary fibrosis can follow a variety of diverse insults including ischemia, respiratory infection, or exposure to ionizing radiation. Consequently, treatments that attenuate [...] Read more.
Fibrosis is a chronic pathology resulting from excessive deposition of extracellular matrix components that leads to the loss of tissue function. Pulmonary fibrosis can follow a variety of diverse insults including ischemia, respiratory infection, or exposure to ionizing radiation. Consequently, treatments that attenuate the development of debilitating fibrosis are in desperate need across a range of conditions. Sphingolipid metabolism is a critical regulator of cell proliferation, apoptosis, autophagy, and pathologic inflammation, processes that are all involved in fibrosis. Opaganib (formerly ABC294640) is the first-in-class investigational drug targeting sphingolipid metabolism for the treatment of cancer and inflammatory diseases. Opaganib inhibits key enzymes in sphingolipid metabolism, including sphingosine kinase-2 and dihydroceramide desaturase, thereby reducing inflammation and promoting autophagy. Herein, we demonstrate in mouse models of lung damage following exposure to ionizing radiation that opaganib significantly improved long-term survival associated with reduced lung fibrosis, suppression of granulocyte infiltration, and reduced expression of IL-6 and TNFα at 180 days after radiation. These data further demonstrate that sphingolipid metabolism is a critical regulator of fibrogenesis, and specifically show that opaganib suppresses radiation-induced pulmonary inflammation and fibrosis. Because opaganib has demonstrated an excellent safety profile during clinical testing in other diseases (cancer and COVID-19), the present studies support additional clinical trials with this drug in patients at risk for pulmonary fibrosis. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Health and Diseases)
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Review

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18 pages, 817 KiB  
Review
Sphingolipids: Less Enigmatic but Still Many Questions about the Role(s) of Ceramide in the Synthesis/Function of the Ganglioside Class of Glycosphingolipids
by Cara-Lynne Schengrund
Int. J. Mol. Sci. 2024, 25(12), 6312; https://doi.org/10.3390/ijms25126312 - 7 Jun 2024
Cited by 1 | Viewed by 1769
Abstract
While much has been learned about sphingolipids, originally named for their sphinx-like enigmatic properties, there are still many unanswered questions about the possible effect(s) of the composition of ceramide on the synthesis and/or behavior of a glycosphingolipid (GSL). Over time, studies of their [...] Read more.
While much has been learned about sphingolipids, originally named for their sphinx-like enigmatic properties, there are still many unanswered questions about the possible effect(s) of the composition of ceramide on the synthesis and/or behavior of a glycosphingolipid (GSL). Over time, studies of their ceramide component, the sphingoid base containing the lipid moiety of GSLs, were frequently distinct from those performed to ascertain the roles of the carbohydrate moieties. Due to the number of classes of GSLs that can be derived from ceramide, this review focuses on the possible role(s) of ceramide in the synthesis/function of just one GSL class, derived from glucosylceramide (Glc-Cer), namely sialylated ganglio derivatives, initially characterized and named gangliosides (GGs) due to their presence in ganglion cells. While much is known about their synthesis and function, much is still being learned. For example, it is only within the last 15–20 years or so that the mechanism by which the fatty acyl component of ceramide affected its transport to different sites in the Golgi, where it is used for the synthesis of Glu- or galactosyl-Cer (Gal-Cer) and more complex GSLs, was defined. Still to be fully addressed are questions such as (1) whether ceramide composition affects the transport of partially glycosylated GSLs to sites where their carbohydrate chain can be elongated or affects the activity of glycosyl transferases catalyzing that elongation; (2) what controls the differences seen in the ceramide composition of GGs that have identical carbohydrate compositions but vary in that of their ceramide and vice versa; (3) how alterations in ceramide composition affect the function of membrane GGs; and (4) how this knowledge might be applied to the development of therapies for treating diseases that correlate with abnormal expression of GGs. The availability of an updatable data bank of complete structures for individual classes of GSLs found in normal tissues as well as those associated with disease would facilitate research in this area. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Health and Diseases)
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15 pages, 1237 KiB  
Review
The Implication of Sphingolipids in Viral Infections
by Sanya Thomas, Stephen Varghese Samuel, Annmarie Hoch, Caitlin Syphurs and Joann Diray-Arce
Int. J. Mol. Sci. 2023, 24(24), 17303; https://doi.org/10.3390/ijms242417303 - 9 Dec 2023
Cited by 6 | Viewed by 2472
Abstract
Sphingolipids are involved in cell signaling and metabolic pathways, and their metabolites play a critical role in host defense against intracellular pathogens. Here, we review the known mechanisms of sphingolipids in viral infections and discuss the potential implication of the study of sphingolipid [...] Read more.
Sphingolipids are involved in cell signaling and metabolic pathways, and their metabolites play a critical role in host defense against intracellular pathogens. Here, we review the known mechanisms of sphingolipids in viral infections and discuss the potential implication of the study of sphingolipid metabolism in vaccine and therapeutic development. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Health and Diseases)
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