Gliomas, the most prevalent and aggressive form of intracranial cancer, account for over 80% of malignant brain tumors, with glioblastoma multiforme (GBM) as the most common and severe subtype (Ostrom et al., 2014). Despite the significant research interest and certain progress in glioma treatment in recent years, the prognosis for patients with gliomas, especially GBM, remains very poor (Ma et al., 2024). The latest fifth edition of the World Health Organization (WHO) tumor classification of the central nervous system (CNS) introduced significant updates, incorporating molecular and genetic parameters for more precise clinical categorization (Louis et al., 2021). Sphingolipids, especially glycosphingolipids, are abundantly in the brain and integral to cell membrane structure and cellular signaling (Hannun and Obeid, 2018). Abnormalities in sphingolipid metabolism have been implicated in promoting gliomas’ aggressiveness, strongly affecting numerous characteristics of tumor phenotype, such as cellular migration, metastasis, and invasiveness (Zaibaq et al., 2022). Their main metabolic enzymes have been actively investigated as new potential targets in glioma therapy development (Wang et al., 2022). The “sphingolipid rheostat” concept highlights the opposing roles of ceramide, which induces apoptosis, and sphingosine-1-phosphate (S1P), which promotes proliferation (Cuvillier et al., 1996). This balance between the pro-apoptotic ceramide and pro-survival S1P is crucial in determining the cell’s fate, and in glioma it is altered towards the pro-survival S1P signaling, promoting uncontrolled cell proliferation and invasiveness (Zaibaq et al., 2022). This mini-review explores the complex and interconnected metabolic effects of sphingolipids in glioma progression, focusing on new achievements in sphingolipid rheostat targeting as an innovative glioma therapy approach, alone or combined with the established current glioma therapies to improve glioma, particularly GBM patient outcomes.

Diffuse gliomas are the most common type of primary CNS tumors in adults (Lucke-Wold et al., 2024; Martin et al., 2023). The fifth edition of the WHO classification of CNS tumors (CNS5) introduced significant changes by adding molecular and genetic markers to the previously histology based classification, making it more precise and clinically relevant (Louis et al., 2021). According to WHO CNS5, there are three main types of adult-type diffuse gliomas: (I) astrocytoma, isocitrate dehydrogenase (IDH)-mutant; (II) oligodendroglioma, IDH-mutant and 1p/19q codeleted; and (III) glioblastoma, IDH-wildtype (Louis et al., 2021; Gisina et al., 2022) (Figure 1). IDH-mutant diffuse astrocytic tumors are considered as astrocytoma, IDH-mutant CNS WHO grades 2, 3, or 4 (Louis et al., 2021). Oligodendrogliomas, IDH-mutant and 1p/19q codeleted are classified as CNS WHO grade 2 or 3 (Louis et al., 2021). IDH-wildtype diffuse astrocytic tumors are now classified as GBM CNS WHO grade 4 if there is microvascular proliferation (MVP) or necrosis and if they meet 1 or more of 3 specific key molecular criteria (Figure 1), even if they show low-grade histological features (Louis et al., 2021). Further evaluation is necessary to classify other IDH-wildtype gliomas that do not meet these molecular criteria (Louis et al., 2021; Meyer et al., 2021). Astrocytoma, IDH-mutant CNS WHO grade 4 are no longer classified as GBMs due to distinct molecular and epigenetic profiles (Figure 1) and different clinical behaviors (Zaibaq et al., 2022; Rajaratnam et al., 2020). The most malignant and aggressive of the adult-type diffuse gliomas are the astrocytoma, IDH-mutant CNS WHO grade 3 and 4, and GBM, IDH-wildtype CNS WHO grade 4, considered higher-grade gliomas (HGG) (Martin et al., 2023). Glioblastoma accounts for nearly 15% of all brain tumors, with approximately 80% being primary tumors, mainly occurring in older patients, while secondary GBMs develop from lower-grade gliomas primarily in younger patients (Louis et al., 2021). Despite aggressive standard therapy, including radical surgery, radiotherapy and temozolomide (TMZ) chemotherapy, and even with adjuvant chemotherapy, the median overall survival of remains 14–20 months (Ma et al., 2024; Stupp et al., 2005). Other therapies, such as carmustine wafers placed in surgical cavity, anti-VEGF antibodies, PDGF and EGFR inhibitors, and immunotherapy, extend survival for only a few months (Norden and Wen, 2006). Recurrence remains nearly inevitable due to GBM’s aggressiveness and therapy resistance, driven by brain tumor-initiating cells (BTICs) (Landis et al., 2018). Lower-grade gliomas, such as astrocytoma, IDH-mutant CNS WHO grade 2 and oligodendroglioma, IDH-mutant and 1q19q codeleted CNS WHO grade 2, have a better prognosis, but their treatment is also challenging as most of them tend to progress to HGG over time (Yu et al., 2020).

Sphingolipids are ubiquitous components of eukaryotic cell membranes, especially abundant in human neural tissue, where they contribute (Gault et al., 2010) to membrane structure and serve as signaling molecules in processes like apoptosis, proliferation, angiogenesis, and vesicular trafficking (Ogretmen, 2017). They are commonly divided into simple, sphingoid bases and ceramides, and complex sphingolipids, such as glycosphingolipids, sphingomyelins and sulphatides (Hannun and Obeid, 2018).

Sphingoid bases, long-chain aliphatic amino alcohols, form the structural backbone of sphingolipids and serve as signaling molecules. Their chain length can vary from 12 to 26 carbons, with sphingosine (d18:1) and sphinganine (d18:0) predominating in mammalian tissue; sphingosine arise from sphingolipid degradation, while sphinganine is a precursor in de novo sphingolipid biosynthesis (Pruett et al., 2008).

Ceramides, bioactive sphingolipids are synthesized by six ceramide synthase isoforms (CERS1-6) which bind fatty acids of varying chain lengths to a sphingoid base, resulting in ceramides with diverse functions and tissue distributions (Riebeling et al., 2003; Raichur, 2020). In human brain tissue, 18-carbon fatty acid ceramides are the most abundant (Pruett et al., 2008). Ceramides are synthesized either de novo or via hydrolysis from complex sphingolipids and are further catabolized by ceramidases to form sphingoid bases, serving as a key intermediates and precursors for all complex sphingolipids (Zheng et al., 2006; Mullen et al., 2012). Bioactive sphingoid bases and ceramides disrupt pro-survival cellular signaling pathways inducing apoptosis by various activating mechanisms (Nganga et al., 2018). Extracellularly oriented ceramides produced by acid sphingomyelinase (sphingomyelin phosphodiesterase 1, SMPD1) in lipid rafts activate membrane receptor clustering with different tumor necrosis factors triggering strong apoptotic signal responses (Dumitru et al., 2009). Intracellularly, ceramides trigger apoptosis by affecting outer mitochondrial membrane permeability and regulating apoptosis-related molecules like phosphatases, kinases, and phospholipase (Gault et al., 2010; Dadsena et al., 2019) During oncogenic transformation, cells often evade apoptosis as ceramidases become more active, hydrolyzing ceramides into sphingosine and fatty acid (Levery, 2005).

Sphingosine kinases 1 and 2 (SPHK1/2) phosphorylate sphingosine to S1P, with SPHK1 being localized in the cytoplasm and SPHK2 in the nucleus, endoplasmic reticulum (ER), mitochondria, and, in cancer cells, in the plasma membrane (Diaz Escarcega et al., 2021). While SPHK1 has mainly pro-survival roles, SPHK2 can promote both pro-apoptotic and pro-survival signals depending on its localization in the cell. SPHK2 can be translocated to the nucleus where the formation of S1P inhibits histone deacetylase 1 and 2 (HDAC1/2) activity, leading to epigenetic changes in gene expression (Diaz Escarcega et al., 2021). Sphingosine-1-phosphate act as a second messenger regulating cell growth, differentiation, migration, and apoptosis by binding to G protein-coupled receptors, S1PR1-5, with variable tissue expression and important roles in development, aging, and pathologies (Merrill, 2011; Sousa et al., 2023; Blaho and Hla, 2014). S1P controls various signaling pathways, including angiogenesis and proliferation, by activating cytosolic effectors, phospholipases, and kinases (Pyne and Pyne, 2000). It is inactivated by ER-enzymes S1P-phosphatases 1 and 2 (SGPP1/2) and phospholipid phosphatases 1–3 (PLPP1-3), or by S1P lyase 1 (SGPL1) localized in the ER and Golgi, but also in plasma membrane, where it directly influences extracellular S1P concentrations (Sousa et al., 2023; Tang and Brindley, 2020) (Figure 2A).

The sphingolipid rheostat concept refers to the balance between pro-apoptotic ceramides and sphingosine, and pro-survival S1P, where ceramide and sphingosine are directly correlated to the downregulation of S1P and vice versa (Cuvillier et al., 1996) (Figure 2A). Bioactive sphingolipid metabolites may serve as biomarkers for cancer malignancy, progression, and metastasis (Newton et al., 2015) (Figure 2B).

Overexpression of SPHK1 and the resulting production of S1P correlated with malignancy, poor prognosis, and shorter survival time in different types of gliomas, especially GBMs (Young and Van Brocklyn, 2007; Li et al., 2022). Increased SPHK1 and decreased SGPP1/2 expression were a hallmark of cultured GBM cells with upregulation of SPHK1 promoting growth and metastasis of GBM cells (Zaibaq et al., 2022; Abuhusain et al., 2013). Upregulated acid ceramidase (N-acyl sphingosine amidohydrolase 1, ASAH1) and SPHK1 were detected in GBM tissues compared to normal brain as well as higher ASAH1 activity in BTICs (Abuhusain et al., 2013). S1P was reported to be, on average, 9-fold higher in GBM tissues compared to normal human brain tissue and correlated with glioma grade, while C18 ceramide was 5-fold lower in GBM tissues (Abuhusain et al., 2013). Fast-proliferating glioblastoma stem cells (GSCs) degrade ceramide and convert sphingosine to S1P more rapidly than slow-proliferating GSCs, and consequently release a significantly higher amount of S1P into the extracellular environment (Marfia et al., 2014). GBM cells and BTICs also release S1P which interacts with S1PRs influencing diverse cellular processes including cell migration, differentiation, proliferation, survival against apoptosis and angiogenesis (Zaibaq et al., 2022; Hawkins et al., 2020; Bassi et al., 2021). Moreover, overexpression of S1PR1-3 is observed in glioma cells (Hawkins et al., 2020). S1P also modulates EGFR expression in both cancer and non-cancer cells (Bassi et al., 2021).

Ceramide is considered a tumor suppressor lipid that can induce anti-proliferative and apoptotic responses in various tumor types, including gliomas (Zaibaq et al., 2022; Bassi et al., 2023). Ceramide levels are often reduced in gliomas due to increased degradation or altered synthesis and are significantly lower in HGG, correlating with malignant progression and poor patient survival (Riboni et al., 2002). The expression of various ceramide types and the balance among them are considered critical for different cancer cell progressions, including glioma. Generally, long-chained ceramides (C16, C18, C20) are considered as pro-apoptotic, while very-long chained ceramides (particularly C24 and C24:1) are associated with proliferative effects (Melero-Fernandez de Mera et al., 2022). In GBM tissue, C18-ceramide levels have been reported to decrease by up to 70%, while reconstitution of C18-ceramide induced cell death in human GBM cells resistant to TMZ (Das et al., 2018).

Recent findings indicate that IDH-wildtype gliomas exhibit a stronger imbalance in sphingolipid rheostat than IDH-mutant gliomas, resulting in elevated ceramide and sphingosine production, which may be the reason why IDH-mutant gliomas are less aggressive than IDH-wildtype (Dowdy et al., 2020). Moreover, several researches have shown that in IDH-mutant gliomas, the sphingolipid balance can be additionally shifted towards increasing pro-apoptotic ceramide production or towards decreasing pro-survival S1P production by targeting enzymes involved in the sphingolipid metabolism like SPHK1/2 and ceramidase, which reduces cancer hallmarks in IDH-mutant gliomas (Zaibaq et al., 2022; Dowdy et al., 2020; Tea et al., 2020) (Figure 2B).

The sphingolipid rheostat is a critical regulator of cell fate in health and disease. In glioma cells, aberrant expression of enzymes of the sphingolipid metabolism leads the cells to escape apoptosis and promote survival and invasiveness. In recent years, several targeted therapies have been proposed that shift the rheostat towards apoptosis and tumor suppression. Targeting the sphingolipid rheostat for glioma treatment provides not only the first-line therapy options for gliomas but is also responsible for sensitizing particular types of gliomas, such as IDH-mutant glioma, for stronger chemotherapeutic response (Dowdy et al., 2020). Given the high complexity of gliomas, particularly GBM, and the limitations of treatment options available so far, a combination of targeting sphingolipid rheostat with some of the current therapies and with genetic profiling for personalized patient selection offers a promising approach to improve outcomes of patients suffering from these vicious tumors.