Irritable bowel syndrome is a gastrointestinal disorder due to multiple pathologies. While patients with this condition experience anxiety and depressed mood more frequently than healthy individuals, it is unclear how gastrointestinal dysfunction interacts with such neuropsychiatric symptoms. Data suggest that irritable bowel syndrome patients predominantly display a lower zinc intake, which presumably impairs enterochromaffin cells producing 5-hydroxytryptamine, gut bacteria fermenting short-chain fatty acids, and barrier system in the intestine, with the accompanying constipation, diarrhea, low-grade mucosal inflammation, and visceral pain. Dyshomeostasis of copper and zinc concentrations as well as elevated pro-inflammatory cytokine levels in the blood can disrupt blood-cerebrospinal fluid barrier function, leading to locus coeruleus neuroinflammation and hyperactivation with resultant amygdalar overactivation and dorsolateral prefrontal cortex hypoactivation as found in neuropsychiatric disorders. The dysregulation between the dorsolateral prefrontal cortex and amygdala is likely responsible for visceral pain-related anxiety, depressed mood caused by anticipatory anxiety, and visceral pain catastrophizing due to catastrophic thinking or cognitive distortion. Collectively, these events can result in a spiral of gastrointestinal symptoms and neuropsychiatric signs, prompting the progression of irritable bowel syndrome. Given that the negative feedback mechanism in regulation of the hypothalamic-pituitary-adrenal axis is preserved in a subset of neuropsychiatric cases, dorsolateral prefrontal cortex abnormality accompanied by neuropsychiatric symptoms may be a more significant contributing factor in brain-gut axis malfunction than activation of the hypothalamic corticotropin-releasing hormone system. The proposed mechanistic model could predict novel therapeutic interventions for comorbid irritable bowel syndrome and neuropsychiatric disorders.

Ulcerative colitis (UC) is a chronic inflammatory gastrointestinal disease typically coexisting with intestinal microbiota dysbiosis, oxidative stress, and an inflammatory response. Although its underlying mechanism of action is unclear, Ma-Mu-Ran Antidiarrheal Capsules (MMRAC) have demonstrated significant therapeutic efficacy for UC.

The mechanism of action of MMRAC in the treatment of UC model was investigated by combining metabolomics, transcriptomics, and intestinal microbiota detection techniques.

The high-dose group of MMRAC was determined as the best therapeutic dose by pathological changes and biochemical indexes. Transcriptome analysis revealed that 360 genes were differentially altered after MMRAC treatment. Metabolomic analysis using colon tissue yielded 14 colon tissue metabolites with significant differences. Intestinal flora analysis showed that 26 major microorganisms were identified at the genus level.

Based on a thorough multi-omics analysis of transcriptomics, metabolomics, and gut flora, it was determined that MMRAC regulated cysteine and methionine metabolism, arginine biosynthesis, and sphingolipid metabolism and their respective genes BHMT, PHGDH, iNOS, and SPHK1, which in turn served to inhibit UC-generated inflammatory responses and oxidative stress. Additionally, MMRAC regulated the abundance of Coprococcus, Helicobacter, Sutterella, Paraprevotella, and Roseburia in the intestinal tracts of UC mice, which was regulated toward normal levels, thereby restoring normal intestinal function.

The purpose of these studies is to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, dedifferentiation of Müller glia (MG), reprogramming into proliferating MG-derived progenitor cells (MGPCs), and neuronal differentiation of the progeny of MGPCs in the chick retina. We found that S1P-related genes are highly expressed by retinal neurons and glia, and levels of expression were dynamically regulated following retinal damage. Drug treatments that activate S1P receptor 1 (S1PR1) or increase levels of S1P suppressed the formation of MGPCs. Conversely, treatments that inhibit S1PR1 or decrease levels of S1P stimulated the formation of MGPCs. Inhibition of S1P receptors or S1P synthesis significantly enhanced the neuronal differentiation of the progeny of MGPCs. We report that S1P-related gene expression in MG is modulated by microglia and inhibition of S1P receptors or S1P synthesis partially rescues the loss of MGPC formation in damaged retinas missing microglia. Finally, we show that TGFβ/Smad3 signaling in the resting retina maintains S1PR1 expression in MG. We conclude that the S1P signaling is dynamically regulated in MG and MGPCs in the chick retina, and activation of S1P signaling depends, in part, on signals produced by reactive microglia.

Sphingolipids are a family of bioactive lipids. The key components include ceramides, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate. Sphingolipids were originally considered to be primarily structural elements of cell membranes but were later recognized as bioactive signaling molecules that play diverse roles in cellular behaviors such as cell differentiation, migration, proliferation, and death. Studies have demonstrated changes in key components of sphingolipids in the kidneys under different conditions and their important roles in the renal function and the pathogenesis of various kidney diseases. This review summarizes the most recent advances in the role of sphingolipid signaling in kidney diseases.

Sphingosine-1-phospate (S1P) receptor agonists (eg, ozanimod) desensitize migrating lymphocytes by irreversibly binding to S1P receptors (S1PR) and triggering their proteasomal degradation. Desensitized lymphocytes cannot sense S1P, therefore, halting lymphocyte recirculation. The S1P lyase (SPL) irreversibly degrades S1P and its inhibition disrupts the S1P gradient. We previously found that systemic SPL inhibitors induce central immunosuppression. Here, we examined whether SPL inhibition may attenuate colitis without systemic immunotoxicity.

We first analyzed SPL expression and localization in mice using qRT-PCR and immunohistochemistry. SPL inhibitors 4-deoxypyridoxine hydrochloride (DOP) and 2-acetyl-4-(tetrahydroxybutyl) imidazole (THI) were used to inhibit SPL systemically, whereas a conditional intestinal epithelial cell (IEC)-specific SPL-deficient mouse was used to evaluate the effects of IEC-specific SPL inhibition on survival, disease activity, histological severity of dextran sulfate sodium-induced colitis, S1P levels, and intestinal permeability.

Sgpl1 mRNA transcripts and protein were ubiquitously expressed in gastrointestinal (GI) tract leukocytes and IEC. Systemic SPL inhibitors did not induce colitis by themselves but depleted CD4+ and CD8+ T cells from blood. However, contrary to its therapeutic effects on ileitis, systemic inhibition reduced survival, accelerated weight loss, worsened histopathological inflammation indices, and tissue damage. We then examined the effects of IEC-specific inhibition on peripheral cell counts and severity of colitis. We found that while it spared peripheral immunity, it similarly hastened colitis. Finally, we examined whether colitis acceleration was due to epithelial barrier compromise after disruption of the S1P gradient. We found that not only systemic but also IEC-specific SPL inhibition increased local S1P levels and led to IEC barrier compromise.

Homeostatic intestinal S1P levels are critical for the regulation of IEC barrier function. Further studies using adaptive immunity-based inflammatory bowel diseases (IBD) models are required to assess the translational value of IEC-specific SPL inhibition as a therapeutic target for human IBD.

The purpose of this study was to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, neuroprotection, and reprogramming of Müller glia (MG) into neurogenic MG-derived progenitor cells (MGPCs) in the adult mouse retina. We found that S1P-related genes were dynamically regulated following retinal damage. S1pr1 (encoding S1P receptor 1) and Sphk1 (encoding sphingosine kinase 1) are expressed at low levels by resting MG and are rapidly upregulated following acute damage. Overexpression of the neurogenic bHLH transcription factor Ascl1 in MG downregulates S1pr1, and inhibition of Sphk1 and S1pr1/3 enhances Ascl1-driven differentiation of bipolar-like cells and suppresses glial differentiation. Treatments that activate S1pr1 or increase retinal levels of S1P initiate pro-inflammatory NFκB-signaling in MG, whereas treatments that inhibit S1pr1 or decreased levels of S1P suppress NFκB-signaling in MG in damaged retinas. Conditional knock-out of NFκB-signaling in MG increases glial expression of S1pr1 but decreases levels of S1pr3 and Sphk1. Conditional knock-out (cKO) of S1pr1 in MG, but not Sphk1, enhances the accumulation of immune cells in acutely damaged retinas. cKO of S1pr1 is neuroprotective to ganglion cells, whereas cKO of Sphk1 is neuroprotective to amacrine cells in NMDA-damaged retinas. Consistent with these findings, pharmacological treatments that inhibit S1P receptors or inhibit Sphk1 had protective effects upon inner retinal neurons. We conclude that the S1P-signaling pathway is activated in MG after damage and this pathway acts secondarily to restrict the accumulation of immune cells, impairs neuron survival and suppresses the reprogramming of MG into neurogenic progenitors in the adult mouse retina.

The glycosylphosphatidylinositol (GPI)-anchored serine proteases, prostasin and testisin, have essential roles in diverse physiological functions including development, reproduction, homeostasis and barrier function of epithelia, angiogenesis, coagulation, and fibrinolysis. Important functions in pathological conditions such as cancer, kidney disease and cardiovascular disease have also been reported. In this review, we summarize current knowledge of the cellular and in vivo roles of prostasin and testisin in physiology and pathophysiology and explore the underlying molecular mechanisms. We discuss how new insights of their role in cancer and cardiovascular disease may facilitate translation into clinical settings in the future.

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.

The purpose of these studies is to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, dedifferentiation of Müller glia (MG), reprogramming into proliferating MG-derived progenitor cells (MGPCs), and neuronal differentiation of the progeny of MGPCs in the chick retina. We found that S1P-related genes are highly expressed by retinal neurons and glia, and levels of expression were dynamically regulated following retinal damage. Drug treatments that activate S1P receptor 1 (S1PR1) or increase levels of S1P suppressed the formation of MGPCs. Conversely, treatments that inhibit S1PR1 or decrease levels of S1P stimulated the formation of MGPCs. Inhibition of S1P receptors or S1P synthesis significantly enhanced the neuronal differentiation of the progeny of MGPCs. We report that S1P-related gene expression in MG is modulated by microglia and inhibition of S1P receptors or S1P synthesis partially rescues the loss of MGPC formation in damaged retinas missing microglia. Finally, we show that TGFβ/Smad3 signaling in the resting retina maintains S1PR1 expression in MG. We conclude that the S1P signaling is dynamically regulated in MG and MGPCs in the chick retina, and activation of S1P signaling depends, in part, on signals produced by reactive microglia.

TRIM14 is an important member of the TRIM family and is widely expressed in a variety of tissues. Like other members of the TRIM family, TRIM14 is also involved in ubiquitination modifications. TRIM14 was initially reported as an interferon-stimulated gene (ISG). In recent years, many studies have focused on the regulatory role of TRIM14 in signaling pathways such as the PI3K/Akt, NF-κB, and cGAS/STING pathways and revealed its mechanism of action in a variety of pathophysiological processes, and the regulation of TRIM14 has attracted the interest of many researchers as a new direction for the treatment of various diseases. However, there are no reviews on the role of TRIM14 in diseases. In this paper, we will describe the structure of TRIM14, review its role in cancer, cardiovascular disease, cervical spondylosis, inflammation and antiviral immunity, and provide an outlook on future research directions.

Head and neck squamous cell carcinoma(HNSCC) is the sixth most common malignancy worldwide, with more than 890,000 new cases and 450,000 deaths annually. Its major risk factors include smoking, alcohol abuse, aging, and poor oral hygiene. Due to the lack of early and effective detection and screening methods, many patients are diagnosed at advanced stages with a five-year survival rate of less than 50%. In this study, we deeply explored the expression of Aging-related genes(ARGs) in HNSCC and analyzed their prognostic significance using single-cell sequencing and spatial transcriptomics analysis. This research aims to provide new theoretical support and directions for personalized treatment. Annually, more than 890,000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed globally, leading to 450,000 deaths, making it the sixth most common malignancy worldwide. The primary risk factors for HNSCC include smoking, alcohol abuse, aging, and poor oral hygiene. Many patients are diagnosed at advanced stages due to the absence of early and effective detection and screening methods, resulting in a five-year survival rate of less than 50%. In this research, single cell sequencing and spatial transcriptome analysis were used to investigate the expression of Aging-related genes (ARGs) in HNSCC and to analyse their prognostic significance. This research aims to provide new theoretical support and directions for personalized treatment.

In this study, we investigated the association between HNSCC and AGRs by utilizing the GSE139324 series in the GEO database alongside the TCGA database, combined with single-cell sequencing and spatial transcriptomics analysis. The data were analyzed using Seurat and tSNE tools to reveal intercellular communication networks. For the spatial transcriptome data, SCTransform and RunPCA were applied to examine the metabolic activities of the cells. Gene expression differences were determined through spacerxr and RCTD tools, while the limma package was employed to identify differentially expressed genes and to predict recurrence rates using Cox regression analysis and column line plots. These findings underscore the potential importance of molecular classification, prognostic assessment, and personalized treatment of HNSCC.

This study utilized HNSCC single-cell sequencing data to highlight the significance of ARGs in the onset and prognosis of HNSCC. It revealed that the proportion of monocytes and macrophages increased, while the proportion of B cells decreased. Notably, high expression of the APOE gene in monocytes was closely associated with patient prognosis. Additionally, a Cox regression model was developed based on GSTP1 and age to provide personalized prediction tools for clinical use in predicting patient survival.

We utilized single-cell sequencing and spatial transcriptomics to explore the cellular characteristics of HNSCC and its interaction with the tumor microenvironment. Our findings reveal that HNSCC tissues show increased mononuclear cells and demonstrate enhanced activity in ARGs, thereby advancing our understanding of HNSCC development mechanisms.

Rheumatoid arthritis (RA) is partially affected by the integrity of the intestinal barrier. Licorice (GC), a medicinal and food-related herb, exhibits potent anti-inflammatory activity; however, studies on its mechanisms of action in RA are limited.

Using a bovine type-II collagen-induced arthritis rat model, this study examined how GC influences the gut-joint axis to decrease RA. The Th17/Treg cell ratios in the blood, colon, and joints were also measured. Metabolomics and 16S rRNA sequencing were applied to explore the effects of variations in gut flora and metabolites.

The arthropathological slices, inflammation markers, and joint inflammation index scores in the GC treatment group significantly differed from those in the CIA group. Studies on the effect of GC on the gut-joint axis showed changes in the levels of lipopolysaccharide and diamine oxidase, both directly associated with intestinal permeability. ZO-1, occludin, and claudin-1, three intestinal tight-junction proteins, may express themselves more when exposed to GC. By maintaining an appropriate Th17/Treg cell ratio in the blood, colon, and joints, GC may reduce impaired to the intestinal barrier. An imbalance in the intestinal microenvironment, caused by modifications in gut flora and endogenous substances, can damage the intestinal barrier. GC may modify the relative abundances of Papillibacter, Clostridium, Eubacterium, Helicobacter, Provotella, and Barnesiella during RA treatment by repairing the intestinal barrier. The metabolic differences were mainly related to primary bile acid biosynthesis, pyrimidine metabolism, steroid biosynthesis, biotin metabolism, and sphingolipid metabolism. A fecal microbiota transplantation experiment confirmed the involvement of the gut microbiota and its metabolites in GC-mediated RA therapy.

The results demonstrated that GC repairs the intestinal barrier and adjusts the gut-joint axis to manage immunological imbalance in RA.

Deregulation of lipid metabolism is one of the most prominent metabolic features in cancer. The activation of sphingolipid metabolic pathways affects the proliferation, invasion, angiogenesis, chemoresistance, and immune escape of tumors, including colorectal cancer (CRC). Dehydrogenase/reductase member 2 (DHRS2), which belongs to the short-chain dehydrogenase/reductase (SDR) family, has been reported to participate in the regulation of lipid metabolism and impact on cancer progression. Trichothecin (TCN) is a sesquiterpenoid metabolite originating from an endophytic fungus of the herbal plant Maytenus hookeri Loes. Studies have shown that TCN exerts a broad-spectrum antitumor activity.

We evaluated the proliferative ability of CRC cells by CCK8 and colony formation assays. A metabolite profiling using liquid chromatography coupled with mass spectrometry (LC/MS) was adopted to identify the proximal metabolite changes linked to DHRS2 overexpression. RNA stability assay and RNA immunoprecipitation (RIP) experiments were applied to determine the post-transcriptional regulation of SPHK1 expression by DHRS2. We used flow cytometry to detect changes in cell cycle and cell apoptosis of CRC cells in the absence or presence of TCN.

We demonstrate that DHRS2 hampers the sphingosine kinases 1 (SPHK1)/sphingosine 1-phosphate (S1P) metabolic pathway to inhibit CRC cell growth. DHRS2 directly binds to SPHK1 mRNA to accelerate its degradation in a post-transcriptionally regulatory manner. Moreover, we illustrate that SPHK1 downregulation induced by DHRS2 contributes to TCN-induced growth inhibition of CRC.

The present study provides a mechanistic connection among metabolic enzymes, metabolites, and the malignant progression of CRC. Moreover, TCN could be developed as a potential pharmacological tool against CRC by the induction of DHRS2 and targeting SPHK1/S1P metabolic pathway.

Extracellular vesicles (EVs) are phospholipid bilayer-enclosed biological particles that are secreted by almost all living cells including animals, plants, and microorganisms. Chinese herbal medicines (CHM) have a long history of using plant-based remedies to treat and prevent human diseases. Chinese herbal medicine-derived extracellular vesicle (CHMEV) generic term refers to nanoscale membrane structures isolated from medicinal plants such as ginseng, ginger, and Panax notoginseng. In recent years, CHMEVs have garnered substantial attention as a novel class of functional components due to their high bioavailability, safety, easy accessibility, and diverse therapeutic effects, indicating their great potential for development as a new dosage form of CHM. Research on CHMEVs in traditional Chinese medicine (TCM) has become a prominent area of interest, opening new avenues for further exploration into the therapeutic effects and functional mechanisms of CHM. Nonetheless, as an emerging field, there is much unknown about these vesicles, and current research remains inconsistent. The review comprehensively summarizes the biogenesis, isolation methods, and physical, and biochemical characterizations of CHMEVs. Additionally, we highlight their biomedical applications as therapeutic agents and drug delivery carriers, including anti-inflammatory, anticancer, regenerative, and antiaging activities. Finally, we propose current challenges and future perspectives. By summarizing the existing literature, we aim to offer valuable clues and inspiration for future CHMEV research, thereby facilitating research standardization of CHMEVs in the treatment of human diseases and drug discovery.

Sphingolipids, particularly sphingosine-1-phosphate (S1P), are bioactive lipids involved in regulating cellular processes such as proliferation, apoptosis, inflammation, and tumor progression. Alkaline ceramidase 2 (ACER2) plays a critical role in sphingolipid metabolism by catalyzing the hydrolysis of ceramide to sphingosine, which is subsequently converted to S1P. Dysregulation of ACER2 has been implicated in various gastrointestinal cancers, including colorectal cancer, gastric cancer, and hepatocellular carcinoma. ACER2-mediated sphingolipid signaling, particularly through the SphK/S1P pathway, influences cancer development by modulating immune responses, inflammation, and the balance between cell survival and death. This review examines the physiological functions of ACER2, and its role in sphingolipid metabolism, and its contribution to the pathogenesis of gastrointestinal cancers. Understanding the mechanisms by which ACER2 regulates tumor progression and immune modulation may open new avenues for targeted therapies in gastrointestinal malignancies.

Hepatic stellate cells (HSCs) play a role in hepatic fibrosis and sphingosine kinase (SphK) is involved in biological processes. As studies on the regulatory mechanisms and functions of SphK in HSCs during liver fibrosis are currently limited, this study aimed to elucidate the regulatory mechanism and connected pathways of SphK upon HSC activation. The expression of SphK1 was higher in HSCs than in hepatocytes, and upregulated in activated primary HSCs. SphK1 was also increased in liver homogenates of carbon tetrachloride-treated or bile duct ligated mice and in transforming growth factor-β (TGF-β)-treated LX-2 cells. TGF-β-mediated SphK1 induction was due to Smad3 signaling in LX-2 cells. SphK1 modulation altered the expression of liver fibrogenesis-related genes. This SphK1-mediated profibrogenic effect was dependent on SphK1/sphingosine-1-phosphate/sphingosine-1-phosphate receptor signaling through ERK. Epigallocatechin gallate blocked TGF-β-induced SphK1 expression and hepatic fibrogenesis by attenuating Smad and MAPK activation. SphK1 induced by TGF-β facilitates HSC activation and liver fibrogenesis, which is reversed by epigallocatechin gallate. Accordingly, SphK1 and related signal transduction may be utilized to treat liver fibrosis.

Sphingosine kinases (SphKs) are a group of important enzymes that circulate at low micromolar concentrations in mammals and have received considerable attention due to the roles they play in a broad array of biological processes including apoptosis, mutagenesis, lymphocyte migration, radio- and chemo-sensitization, and angiogenesis. In the present study, we constructed three classification models by four machine learning (ML) algorithms including naive bayes (NB), support vector machine (SVM), logistic regression, and random forest from 395 compounds. The generated ML models were validated by fivefold cross validation. Five different scaffold hit fragments resulted from SVM model-based virtual screening and docking results indicate that all the five fragments exhibit common hydrogen bond interaction a catalytic residue of SphK1. Further, molecular dynamics (MD) simulations and binding free energy calculation had been carried out with the identified five fragment leads and three cocrystal inhibitors. The best 15 fragments were selected. Molecular dynamics (MD) simulations showed that among these compounds, 7 compounds have favorable binding energy compared with cocrystal inhibitors. Hence, the study showed that the present lead fragments could act as potential inhibitors against therapeutic target of cancers and neurodegenerative disorders.

Angelica sinensis (Oliv.) Diels (AS) is a commonly used herbal medicine and culinary spice known for its gastrointestinal protective properties. Angelica sinensis oil (AO) is the main bioactive component of AS. However, the therapeutic effects and mechanisms of AO on the gastrointestinal tract remain unclear. In this study, we aim to investigated the potential of AO in restoring gut microbiota disorder and metabolic disruptions associated with ulcerative colitis (UC). A systematic chemical characterization of AO was conducted using GC×GC-Q TOF-MS. A UC mouse model was established by freely drinking DSS to assess the efficacy of AO. Utilizing 16 S rRNA sequencing in combination with untargeted metabolomics analysis of serum, we identified alterations in gut microbiota, differential metabolites, and pathways influenced by AO in UC treatment, thereby elucidating the therapeutic mechanism of AO in UC management. Pharmacodynamic results indicated that AO effectively inhibited the content of inflammation mediators, such as Interleukin-1β, Interleukin-6 and tumor necrosis factor-α, and proserved colon tissue integrity in UC mice. Furthermore, AO significantly downregulated the abundance of pathogenic bacteria (Bacteroidetes, Proteobacteria, and Desulfobacteriaceae) while increasing the abundance of beneficial bacteria (Firmicutes, Blautia, Akkermansia, and Lachnospiraceae). Metabolomics analysis highlighted significant disruptions in endogenous metabolism in UC mice, with a notable restoration of SphK1 and S1P levels following AO administration. Besides, we discovered that AO regulated the balance of sphingolipid metabolism and protected the intestinal barrier, potentially through the SphK1/MAPK signaling pathway. Overall, this study indicated that AO effectively ameliorates the clinical manifestations of UC by synergistically regulating gut microbe and metabolite homeostasis. AO emerges as a potential functional and therapeutic ingredient for UC treatment.

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC) are chronic immune-mediated diseases which primarily target the intestines. In recent years, the development and regulatory approval of various immunotherapies, both biological agents and small molecules, that target specific pathways of the IBD-associated inflammatory cascade have revolutionized the treatment of IBD. Small molecules offer the advantages of oral administration and short wash-out times. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of ceramide, which exerts its functions after binding to five G-protein-coupled receptors (S1PR1-S1PR5). Concerning IBD, S1P participates in the egress of lymphocytes from the secondary lymphoid tissue and their re-circulation to sites of inflammation, mainly through S1PR1 binding. In addition, this system facilitates the differentiation of T-helper cells towards proinflammatory immunophenotypes. Recently, S1P modulators have offered a valuable addition to the IBD treatment armamentarium. They exert their anti-inflammatory function via sequestration of T cell subsets in the lymphoid tissues and prevention of gut homing. In this review, we revisit the role of the S1P/S1PR axis in the pathogenesis of IBD and discuss efficacy and safety data from clinical trials and real-world reports on the two S1PR modulators, ozanimod and etrasimod, that are currently approved for IBD treatment, and comment on their potential positioning in the IBD day-to-day management. We also present recent data on emerging S1P modulators. Finally, based on the successes and failures of S1PR modulators in IBD, we discuss future avenues of IBD treatments targeting the S1P/S1PR axis.

Ulcerative colitis (UC) is a type of inflammatory bowel disease associated with persistent inflammation. Animal studies proved the efficacy of metformin in UC.

To investigate the potential role of metformin and its protective pathways in patients with UC.

This is a randomized, controlled, and double-blinded clinical trial that included 60 participants with mild to moderate UC and was divided randomly into two groups (n = 30). For 6 months, the mesalamine group received 1 g of mesalamine three times daily (t.i.d.). For six months, the metformin group received mesalamine 1 g t.i.d. and metformin 500 mg twice daily. A gastroenterologist evaluated patients at baseline and 6 months after starting the treatment in order to measure serum levels of zonulin, sphingosine 1 phosphate (S1P), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Biopsies from the colon were used to measure gene expression of zonula occuldin-1 (ZO-1), signal transducer and activator of factor-3 (STAT-3), and intracellular adhesion molecule-1 (ICAM-1). The numeric pain rating scale (NRS) and partial Mayo score were also assessed for each patient.

When compared to the mesalamine group, the metformin group demonstrated a statistical decrease in serum IL-6, zonulin, TNF-α, SIP, gene expression of ICAM-1 and STAT-3, and a significant increase in colonic ZO-1 when compared to the mesalamine group. The metformin group also showed a significant decrease in NRS and partial Mayo score index in comparison with the mesalamine group.

Metformin may be a promising additional therapy for UC patients. Trial registration identifier: NCT05553704.

Resistance to platinum-based chemotherapy is the major cause of poor prognosis and cancer-associated mortality in ovarian cancer patients, so novel therapeutic strategies to restore platinum sensitivity are needed to improve patient outcomes. Sphingosine Kinase (SphK) 1 is involved in regulating multiple pro-survival pathways, key mediators in the sensitivity of tumor cells toward platinum. By encapsulating CBP and the SphK1 inhibitor PF543 in PLGA (poly lactic-co-glycolic acid) nanoparticles, a dual-drug delivery system (C/PNPs) was formed to simultaneously deliver CBP and PF543. The physicochemical characteristics, cell uptake rate and biodistribution behavior of C/PNPs were evaluated. Then the anti-tumor ability of C/PNPs in vitro and in vivo was further investigated. The C/PNPs could deliver CBP and PF543 simultaneously to a platinum-insensitive cell line (SKOV3) both in vitro and in vivo. Furthermore, benefiting from the enhanced permeability and retention (EPR) effect of PLGA NPs, C/PNPs exhibited an improved tumor region accumulation. As a result, a synergistic anti-tumor effect was found in the SKOV3 tumor-bearing mice, with tumor volume inhibiting rates of 84.64% and no side effects in major organs. The mechanistic studies confirmed that the inhibition of SphK1 by PF543 sensitized SKOV3 cells to CBP chemotherapy, partly by inhibiting the CBP-induced activation of pro-survival pathways, including ERK, AKT and STAT3 signaling. Our study reveals that C/PNPs can serve as an efficient dual-drug delivery system to restore platinum sensitivity in ovarian cancer models partly through inhibiting platinum-induced pro-survival pathway activation.

The incidence of inflammatory bowel disease (IBD) has increased over the last 20 years. A variety of causes, both physiological and environmental, contribute to the initiation and progression of IBD, making disease management challenging. Current treatment options target various aspects of the immune response to dampen intestinal inflammation; however, their effectiveness at retaining remission, their side effects, and loss of response from patients over time warrant further investigation. Finding a common thread within the multitude causes of IBD is critical in developing robust treatment options. Sphingolipids are evolutionary conserved bioactive lipids universally generated in all cell types. This diverse lipid family is involved in a variety of fundamental, yet sometimes opposing, processes such as proliferation and apoptosis. Implicated as regulators in intestinal diseases, sphingolipids are a potential cornerstone in understanding IBD. Herein we will describe the role of host- and microbial-derived sphingolipids as they relate to the many factors of intestinal health and IBD.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cancer, accounting for approximately 80% of all renal cell cancers. Due to its exceptional inter- and intratumor heterogeneity, it is highly resistant to conventional systemic therapies. Targeting the evasion of cell death, one of cancer's hallmarks, is currently emerging as an alternative strategy for ccRCC. In this article, we review the current state of apoptosis-inducing therapies against ccRCC, including antisense oligonucleotides, BH3 mimetics, histone deacetylase inhibitors, cyclin-kinase inhibitors, inhibitors of apoptosis protein antagonists, and monoclonal antibodies. Although preclinical studies have shown encouraging results, these compounds fail to improve patients' outcomes significantly. Current evidence suggests that inducing apoptosis in ccRCC may promote tumor progression through apoptosis-induced proliferation, anastasis, and apoptosis-induced nuclear expulsion. Therefore, re-evaluating this approach is expected to enable successful preclinical-to-clinical translation.

Glioblastoma is the most common and aggressive type of malignant brain tumor with a poor prognosis due to the lack of effective treatment options. Therefore, new treatment options are required. Sphingolipids are essential components of the cell membrane, while complement components are integral to innate immunity, and both play a critical role in regulating glioblastoma survival signaling. This review focuses on recent studies investigating the functional roles of sphingolipid metabolism and complement activation signaling in glioblastoma. It also discusses how targeting these two systems together may emerge as a novel therapeutic approach.

The link between inflammation and cancer is well documented and colonic inflammation caused by inflammatory bowel disease (IBD) is thought to be a high-risk factor for the development of colorectal cancer (CRC). The complex crosstalk between epithelial and inflammatory cells is thought to underlie the progression from inflammation to cancer. The present review collates and summarises recent advances in the understanding of the pathogenesis of IBD-associated CRC (IBD-CRC), including the oncogenic mechanisms of the main inflammatory signalling pathways and genetic alterations induced by oxidative stress during colonic inflammation, and discusses the crosstalk between the tumour microenvironment, intestinal flora and host immune factors during inflammatory oncogenesis in colitis-associated CRC. In addition, the therapeutic implications of anti-inflammatory therapy for IBD-CRC were discussed, intending to provide new insight into improve clinical practice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with growing incidence worldwide. Our group reported the compound 5-choro-1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01007) as H4R antagonist (pKi 6.2) and therefore the effects and pharmacological efficacy on a DSS-induced mice model of UC were assessed in this work. Experimental acute colitis was induced in male BALB/c mice (n = 5-10) by administering 3 % DSS in the drinking water for six days. The test compound LINS01007 was administered daily i.p. (5 mg/kg) and compared to control group without treatment. Body weight, water and food consumption, and the presence of fecal blood were monitored during 7-day treatment period. The levels of inflammatory markers (PGE2, COX-2, IL-6, NF-κB and STAT3) were also analyzed. Animals subjected to the acute colitis protocol showed a reduction in water and food intake from the fourth day (p < 0.05) and these events were prevented by LINS01007. Histological signs of edema, hyperplasia and disorganized intestinal crypts, as well as neutrophilic infiltrations, were found in control mice while these findings were significantly reduced in animals treated with LINS01007. Significant reductions in the levels of PGE2, COX-2, IL-6, NF-κB and STAT3 were observed in the serum and tissue of treated animals. The results demonstrated the significant effects of LINS01007 against DSS-induced colitis, highlighting the potential of H4R antagonism as promising treatment for this condition.

Cancer prognosis remains a critical clinical challenge. Lipidomic analysis via mass spectrometry (MS) offers the potential for objective prognostic prediction, leveraging the distinct lipid profiles of cancer patient-derived specimens. This review aims to systematically summarize the application of MS-based lipidomic analysis in prognostic prediction for cancer patients. Our systematic review summarized 38 studies from the past decade that attempted prognostic prediction of cancer patients through lipidomics. Commonly analyzed cancers included colorectal, prostate, and breast cancers. Liquid (serum and urine) and tissue samples were equally used, with liquid chromatography-tandem MS being the most common analytical platform. The most frequently evaluated prognostic outcomes were overall survival, stage, and recurrence. Thirty-eight lipid markers (including phosphatidylcholine, ceramide, triglyceride, lysophosphatidylcholine, sphingomyelin, phosphatidylethanolamine, diacylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylethanolamine, lysophosphatidic acid, dihydroceramide, prostaglandin, sphingosine-1-phosphate, phosphatidylinosito, fatty acid, glucosylceramide and lactosylceramide) were identified as prognostic factors, demonstrating potential for clinical application. In conclusion, the potential for developing lipidomics in cancer prognostic prediction was demonstrated. However, the field is still nascent, necessitating future studies for validating and establishing lipid markers as reliable prognostic tools in clinical practice.

Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies.

Primary hepatocellular carcinoma (HCC) is one of the most common malignant tumors, but its pathogenesis remains incompletely elucidated. Recently, many studies indicated that lipid remodeling plays an important role in the occurrence and development of HCC. Furthermore, lipids have been proven to be indispensable mediators in promoting communication between tumor cells and extracellular matrix in the tumor microenvironment. Thus, this study aims to comprehensively investigate the process of lipid remodeling during HCC metastasis based on the LC-electrospray ionization-MS (LC-ESI-MS) combined with multiple reaction monitoring technology. M2 tumor-associated macrophages and the recombinant human protein CXCL2 were used to simulate the tumor microenvironment. After co-incubating SMMC7721 and MHCC97-H cell lines with M2 tumor-associated macrophages or the recombinant human protein CXCL2 for 48 h, LC-ESI-MS was used to quantify the levels of two major classes of lipid molecules, namely, glycerophospholipids and sphingolipids. Our results suggest that lipid remodeling in the tumor microenvironment may promote the migration and invasion of HCC cell lines.

Colitis-associated intestinal cancer (CAC) can develop in patients with inflammatory bowel disease; however, the malignant grade of CAC may differ from that of sporadic colorectal cancer (CRC). Therefore, we compared histological findings distinct from cancer stage between CAC and sporadic CRC to evaluate the features of CAC.

We reviewed the clinical and histological data collected from a nationwide database in Japan between 1983 and 2020. Patient characteristics were compared to distinguish ulcerative colitis (UC), Crohn's disease (CD), and sporadic CRC. Comparisons were performed by using all collected data and propensity score-matched data.

A total of 1077 patients with UC-CAC, 297 with CD-CAC, and 136 927 with sporadic CRC were included. Although the prevalence of well or moderately differentiated adenocarcinoma (Tub1 and Tub2) decreased according to tumor progression for all diseases (P < 0.01), the prevalence of other histological findings, including signet ring cell carcinoma, mucinous carcinoma, poorly differentiated adenocarcinoma, or squamous cell carcinoma, was significantly higher in CAC than in sporadic CRC. Based on propensity score-matched data for 982 patients with UC and 268 with CD, the prevalence of histological findings other than Tub1 and Tub2 was also significantly higher in those with CAC. At pT4, mucinous carcinoma occurred at a significantly higher rate in patients with CD (45/86 [52.3%]) than in those with sporadic CRC (13/88 [14.8%]) (P < 0.01).

CAC, including early-stage CAC, has a higher malignant grade than sporadic CRC, and this difference increases in significance with tumor progression.

Intensified sanitation practices amid the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak might result in the increased release of chloramine disinfectants into surface water, significantly promoting the formation of nitrosamine disinfection by-products (DBPs) in drinking water. Unfortunately, these nitrosamine DBPs exhibit significant genotoxic, carcinogenic, and mutagenic properties, whereas chlorinating disinfectants remain in global practice. The current review provides valuable insights into the occurrence, identification, contamination status, exposure limits, and toxicity of the new unregulated disinfection by-products (nitrosamine DBPs) in drinking water. As a result, concentrations of nitrosamine DBPs far exceed allowable limits in drinking water, and prolonged exposure has the potential to cause metabolic disorders, a critical step in tumor initiation and progression. Importantly, based on recent research, we have concluded the role of nitrosamines DBPs in different metabolic pathways. Remarkably, nitrosamine DBPs can induce chronic inflammation and initiate tumors by activating sphingolipid and polyunsaturated fatty acid metabolism. Regarding amino acid and nucleotide metabolism, nitrosamine DBPs can inhibit tryptophan metabolism and de novo nucleotide synthesis. Moreover, inhibition of de novo nucleotide synthesis fails to repair DNA damage induced by nitrosamines. Additionally, the accumulation of lactate induced by nitrosamine DBPs may act as a pivotal signaling molecule in communication within the tumor microenvironment. However, with the advancement of tumor metabolomics, understanding the role of nitrosamine DBPs in causing cancer by inducing metabolic abnormalities significantly lags behind, and specific mechanisms of toxic effects are not clearly defined. Urgently, further studies exploring this promising area are needed.

Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids. We elucidated that the primary mechanism of anti-tumour activity conferred by bazedoxifene treatment occurs via pro-apoptotic responses in tumour cells. Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression.

In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients. However, recurrent and metastatic breast cancer often eventually develops resistance to these drugs, and cure is still rare. As such, the development of new therapies for refractory breast cancer that differ from conventional mechanisms of action is necessary. Sphingosine-1-phosphate (S1P) is a key molecule with a variety of bioactive activities, including involvement in cancer cell proliferation, invasion, and metastasis. S1P also contributes to the formation of the cancer microenvironment by inducing surrounding vascular- and lymph-angiogenesis and regulating the immune system. In this article, we outline the basic mechanism of action of S1P, summarize previous findings on the function of S1P in cancer cells and the cancer microenvironment, and discuss the clinical significance of S1P in breast cancer and the therapeutic potential of targeting S1P signaling.

Inflammation is an important immune response of the body. It is a physiological process of self-repair and defense against pathogens taken up by biological tissues when stimulated by damage factors such as trauma and infection. Inflammation is the main cause of high morbidity and mortality in most diseases and is the physiological basis of the disease. Targeted therapeutic strategies can achieve efficient toxicity clearance at the inflammatory site, reduce complications, and reduce mortality. Sphingosine-1-phosphate (S1P), a lipid signaling molecule, is involved in immune cell transport by binding to S1P receptors (S1PRs). It plays a key role in innate and adaptive immune responses and is closely related to inflammation. In homeostasis, lymphocytes follow an S1P concentration gradient from the tissues into circulation. One widely accepted mechanism is that during the inflammatory immune response, the S1P gradient is altered, and lymphocytes are blocked from entering the circulation and are, therefore, unable to reach the inflammatory site. However, the full mechanism of its involvement in inflammation is not fully understood. This review focuses on bacterial and viral infections, autoimmune diseases, and immunological aspects of the Sphks/S1P/S1PRs signaling pathway, highlighting their role in promoting intradial-adaptive immune interactions. How S1P signaling is regulated in inflammation and how S1P shapes immune responses through immune cells are explained in detail. We teased apart the immune cell composition of S1P signaling and the critical role of S1P pathway modulators in the host inflammatory immune system. By understanding the role of S1P in the pathogenesis of inflammatory diseases, we linked the genomic studies of S1P-targeted drugs in inflammatory diseases to provide a basis for targeted drug development.

Inflammatory bowel disease (IBD), characterized by chronic inflammation in the intestinal tract, increases the risk for the development of colorectal cancer (CRC). Sphingolipids, which have been implicated in IBD and CRC, are a class of bioactive lipids that regulate cell signaling, differentiation, apoptosis, inflammation, and survival. The balance between ceramide (Cer), the central sphingolipid involved in apoptosis and differentiation, and sphingosine-1-phosphate (S1P), a potent signaling molecule involved in proliferation and inflammation, is vital for the maintenance of normal cellular function. Altered sphingolipid metabolism has been implicated in IBD and CRC, with many studies highlighting the importance of S1P in inflammatory signaling and pro-survival pathways. A myriad of sphingolipid analogues, inhibitors, and modulators have been developed to target the sphingolipid metabolic pathway. In this review, the efficacy and therapeutic potential for modulation of sphingolipid metabolism in IBD and CRC will be discussed.

Cinnamaldehyde (CAH), a phytochemical constituent isolated from cinnamon, is gaining attention due to its nutritional and medicinal benefits. This study aimed to investigate the potential role of CAH in the treatment of ulcerative colitis (UC).

Integrated metabolomics and gut microbiome analysis are performed for 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced UC rats. The effect of CAH on colonic inflammation, lipid peroxidation, metabolic profiles, and gut microbiota is systematically explored. It finds that CAH improves the colitis-related symptoms, decreases disease activity index, increases the colon length and body weight, and alleviates histologic inflammation of UC rats. These therapeutic effects of CAH are due to suppression of inflammation and lipid peroxidation. Moreover, multi-omics analysis reveals that CAH treatment cause changes in plasma metabolome and gut microbiome in UC rats. CAH regulates lipid metabolic processes, especially phosphatidylcholines, lysophosphatidylcholines, and polyunsaturated fatty acids. Meanwhile, CAH modulates the gut microbial structure by restraining pathogenic bacteria (such as Helicobacter) and increasing probiotic bacteria (such as Bifidobacterium and Lactobacillus).

These results indicate that CAH exerts a beneficial role in UC by synergistic modulating the balance in gut microbiota and the associated metabolites, and highlights the nutritional and medicinal value of CAH in UC management.

Studies have demonstrated that activated pancreatic stellate cells (PSCs) play a crucial role in pancreatic fibrogenesis in chronic pancreatitis (CP); however, the precise mechanism for PSCs activation has not been fully elucidated. We analyzed the role of injured pancreatic acinar cells (iPACs) in the activation of PSCs of CP.

Sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling was evaluated in experimental CP induced by cerulein injection or pancreatic duct ligation, as well as in PACs injured by cholecystokinin. The activation of PSCs and pancreatic fibrosis in CP samples was evaluated by immunohistochemical and immunofluorescence analyses. In vitro coculture assay of iPACs and PSCs was created to evaluate the effect of the SPHK1/S1P pathway and S1P receptor 2 (SIPR2) on autophagy and activation of PSCs. The pathogenesis of CP was assessed in SPHK1-/- mice or PACs-specific SPHK1-knockdown mice with recombinant adeno-associated virus serotypes 9-SPHK1-knockdown, as well as in mice treated with inhibitor of SPHK1 and S1P receptor 2 (S1PR2).

SPHK1/S1P was remarkably increased in iPACs and acinar cells in pancreatic tissues of CP mice. Meanwhile, the pathogenesis, fibrosis, and PSCs activation of CP was significantly prevented in SPHK1-/- mice and recombinant adeno-associated virus serotypes 9-SPHK1-knockdown mice. Meanwhile, iPACs obviously activated PSCs, which was prevented by SPHK1 knockdown in iPACs. Moreover, iPACs-derived S1P specifically combined to S1PR2 of PSCs, by which modulated 5' adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin pathway and consequently induced autophagy and activation of PSCs. Furthermore, hypoxia-inducible factor 1-α and -2α promoted SPHK1 transcription of PACs under hypoxia conditions, which is a distinct characteristic of the CP microenvironment. Coincidently, inhibition of SPHK1 and S1PR2 activity with inhibitor PF-543 and JTE-013 obviously impeded pancreatic fibrogenesis of CP mice.

The activated SPHK1/S1P pathway in iPACs induces autophagy and activation of PSCs by regulating the S1PR2/5' adenosine monophosphate-activated protein kinase/mammalian target of rapamycin pathway, which promotes fibrogenesis of CP. The hypoxia microenvironment might contribute to the cross talk between PACs and PSCs in pathogenesis of CP.

Feline mammary carcinoma (FMC) is one of the most prevalent malignancies of female cats. FMC is highly metastatic and thus leads to poor disease outcomes. Among all metastases, liver metastasis occurs in about 25% of FMC patients. However, the mechanism underlying hepatic metastasis of FMC remains largely uncharacterized.

Herein, we demonstrate that FMC-derived extracellular vesicles (FMC-EVs) promotes the liver metastasis of FMC by activating hepatic stellate cells (HSCs) to prime a hepatic premetastatic niche (PMN). Moreover, we provide evidence that sphingosine kinase 1 (SK1) delivered by FMC-EV was pivotal for the activation of HSC and the formation of hepatic PMN. Depletion of SK1 impaired cargo sorting in FMC-EV and the EV-potentiated HSC activation, and abolished hepatic colonization of FMC cells.

Taken together, our findings uncover a previously uncharacterized mechanism underlying liver-metastasis of FMC and provide new insights into prognosis and treatment of this feline malignancy.

Sphingolipids are essential components of all eukaryotic membranes. The bioactive sphingolipid molecule, Sphingosine 1-Phosphate (S1P), regulates various important biological functions. This review aims to provide a comprehensive overview of the role of S1P signaling pathway in various immune cell functions under different pathophysiological conditions including bacterial and viral infections, autoimmune disorders, inflammation, and cancer. We covered the aspects of S1P pathways in NOD/TLR pathways, bacterial and viral infections, autoimmune disorders, and tumor immunology. This implies that targeting S1P signaling can be used as a strategy to block these pathologies. Our current understanding of targeting various components of S1P signaling for therapeutic purposes and the present status of S1P pathway inhibitors or modulators in disease conditions where the host immune system plays a pivotal role is the primary focus of this review.