In a previous study, S1P levels measured by HPLC were elevated in human fibrotic livers, accompanied by an increased expression level of S1PR1 and S1PR3 in myofibroblasts (65, 66). This may be ascribed to the upregulation of S1PR1 and S1PR3, facilitating the differentiation of bone marrow mesenchymal stem cells (BMSC) into myofibroblasts (67). S1PR1/3 antagonists can attenuate the degree of liver fibrosis by suppressing the up-regulation of angiogenesis markers in the damaged liver (65). In addition, S1PR2-siRNA can alleviate liver fibrosis and inflammation by inhibiting the formation of neutrophil extracellular traps (NET) in fatty liver model mice (68). During the early stages of chronic liver disease, S1PR2-mediated activation of neutrophils is implicated in the progression of liver injury and may potentially serve as a novel therapeutic target for cholestatic liver disease (69). Inflammation driven by the NLRP3 inflammasome is a key trigger of liver fibrosis during cholestatic liver injury (70). S1P promotes the activation of the NLRP3 inflammasome and the secretion of pro-inflammatory cytokines (IL-1β and IL-18) through the S1PR2/Gα pathway (71). Treatment with JTE-013, an S1PR2 inhibitor, significantly limited the initiation and activation of the NLRP3 inflammasome in cholestatic liver injury (40, 71). In conclusion, different S1P/S1PR pathways exert distinct effects at various stages of liver fibrosis.

The development of Nonalcoholic steatohepatitis (NASH) is linked to endoplasmic reticulum (ER) stress and necessitates the co-localization of Caspase-2 with S1P (72). Thus, the interrelationship between lipid accumulation, cytokines, and lysophospholipids plays a central role in the pathogenesis of NASH (72). In a mouse model of NASH, liver S1P levels and Sphk1 levels were increased (73). Reem Rida et al. pointed out using HepG2 cells that FTY720P binds to S1PR3 and sequentially activates Gq and phosphatidylinositol 3-kinase (PI3K), which can promote lipid accumulation (73). In an experimental NASH animal model, S1PR1 knockdown inhibited saturated fat-induced NF-κB signaling and decreased the mRNA expression level of TNFα and monocyte chemoattractant protein 1 (MCP1) in HepG2 cells (74). The role of S1P in steatohepatitis is highlighted by the fact that the administration of S1P antagonists to experimental NASH animals eradicates the disease (75). Taken together, these data establish a mechanistic link between sphingolipid signaling and hepatic lipid accumulation and inflammation in NASH, providing valuable insights for the treatment of this disease.

S1P has been shown to promote cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in Hepatocellular carcinoma (HCC) (60). In an in vitro experiment, the HCC cell line HepG2 was found to secrete S1P, thereby preventing cell proliferation (76). FTY720 not only exerts potent antiangiogenic effects but is also cytotoxic to cancer cells and has been found to effectively inhibit the proliferation of numerous cancer cells (77). At present, FTY720 is regarded as a novel immunosuppressant with potent anticancer properties (78) In the MCA-RH7777 hepatocellular carcinoma cell line model, FTY720 reduced intrahepatic and pulmonary metastases as well as tumorigenesis, possibly through its function as an S1PR1 modulator (79). FTY720 also induced apoptosis in HCC cells by activating protein kinase Cδ signaling (80). In addition, FTY720 inhibited the invasion and proliferation of HCC by down-regulating S1PR1 expression and inhibited the recurrence of HCC after liver transplantation (81). Lastly, Fty720 significantly prolonged the life span of rats with cancerous liver and non-cancerous liver transplantation, highlighting its role in lowering the risk of recurrence and prolonging survival in cancer patients following liver transplantation (81).

Cholestasis is generally associated with sepsis (5). Early liver dysfunction (plasma bilirubin >2 mg/dL) was observed in 11% of critically ill patients in a large prospective multicenter study and was identified as a strong independent risk factor for late mortality (82). During sepsis, the liver is attacked by pathogens, toxins, or inflammatory mediators, and pathological changes can progress from hepatocyte dysfunction to liver injury, eventually culminating in liver failure (83). Liver dysfunction frequently occurs during the early phase of sepsis, primarily due to inflammation and hypoperfusion (84, 85). At the same time, inflammation also triggers the formation of ROS, leading to oxidative stress (86). Septic liver injury is characterized by the following clinical features: hypoxic hepatitis, sepsis-related cholestasis, and hyperbilirubinemia (7). On the one hand, persistent hepatic ischemia, hypoxia and inflammation cause oxygen metabolism within liver cells (87). On the other hand, energy deficiency, endotoxin, or proinflammatory cytokines may cause cholestatic hepatocyte injury by disrupting the outflow and excretion of bile (88). Besides, the hepatobiliary excretion mechanism is particularly sensitive to inflammation ( Figure 1 ), which increases vulnerability to disruption in bile metabolism post-infection. A vicious cycle may be formed upon endotoxin-induced cholestasis, leading to a decrease in bile acid concentration in the small intestine, thereby driving bacterial translocation and endotoxin absorption and further aggravating cholestasis (89).

Recent studies have concluded that S1P is associated with certain models of acute liver injury (90). Nevertheless, although S1P has been documented to contribute to liver injury in the majority of studies, it may exert protective effects in others. For instance, S1P participates in the recruitment and activation of immune cells during liver injury (71). However, in vitro studies have revealed that S1P protects hepatocytes from apoptotic injury (91).

Hyperactivation of the immune system is a common cause of acute organ injury, including the liver, wherein various liver-resident immune cells, such as Kupffer cells (KCS), liver natural killer T (NKT), and dendritic cells, play an instrumental role (92). This inflammatory cascade not only eliminates bacteria but also damages the liver (93). In an in situ perfusion experiment in piglets, endotoxins caused only pulmonary hypertension and neutropenia, while the levels of tumor necrosis factor α (TNF-α), interleukin (IL) -6, and nitric oxide (NO) were elevated when perfused into the lungs alone, without causing pulmonary edema (94). However, when the liver was included in the perfusion, the endotoxins caused marked hypoxemia and pulmonary edema with significant increases in the levels of TNF-α, IL-6, and NO (94). These findings conjointly suggest that the liver is a major source of cytokine and NO production following exposure to endotoxins (5).

S1P is a chief component in regulating the transport and activation of several immune cells (23). As an important immune organ in the body, the S1P signal transduction pathway is also involved in inflammatory liver injury (23). Indeed, in LPS/D-galactosamine (D-Gal)-induced liver failure, S1P levels were elevated, whilst the expression of SphK1, S1PR1, and S1PR3 was upregulated in the liver, and the levels of serum markers of liver failure, AST and ALT, and the serum cytokines TNF-α, IL-1, and IL-6 were increased (25). We speculate that SphK1 may play up-regulate the expression of S1P in peripheral blood monocytes, Kupffer cells, and liver resident macrophages (95). Treatment with the pan-SPHK inhibitor N, N-dimethylsphingosine reduced mortality in mice with sepsis-induced liver injury, as well as decreased liver inflammation and cell death (96). Furthermore, the Spns2/S1P signaling pathway has been shown to play a regulatory role at different stages of the inflammatory response. Specifically, the Spns2/S1P signaling pathway regulates the intensity of macrophage-mediated inflammation via the lactate-ROS axis during the early stages of sepsis (97). At later stages, it maintains the antimicrobial response of macrophages. Consequently, enhancing this pathway may restore the balance in immune responses during sepsis and prevent early hyperinflammation and late-stage immunosuppression (97). A previous study indicated that down-regulating the SPHK1/S1P/S1PR1 pathway can inhibit inflammation and oxidative stress, thereby relieving LPS-induced acute liver injury (25). Another study postulated that S1PR2 deficiency mediates the type 2 immune response and alleviates sepsis-induced lung injury by promoting IL-33 release from macrophages (98). Meanwhile, both S1PR2 gene deletion and pharmacological inhibition of S1PR2 significantly limited bacterial load, enhanced macrophage phagocytosis, and improved the survival rate of septic mice (99). It is worthwhile emphasizing that S1P promotes the activation of the NLRP3 inflammasome and contributes to the secretion of IL-1β and IL-18 in bone marrow-derived macrophages through S1PR2 (100). Conversely, S1PR2 knockdown inhibits the activation of the NLRP3 inflammasome in bone marrow-derived macrophages and alleviates liver inflammation (71, 100). Inhibition of S1PR3 can inhibit ATP-induced NLRP3 inflammasome activation in macrophages through TWIK2-mediated potassium efflux (101). Therefore, different S1PRs may operate together to optimize innate immunity and manage infection during sepsis.

In addition to macrophages, NK cells have been extensively studied. They constitute an important innate immune cell population in the liver, accounting for 30%-40% and 10%-20% of total intrahepatic lymphocytes in humans and mice, respectively (102). Importantly, NK cells play a critical role in the first-line innate defense and immune surveillance of the liver by eliminating invading pathogens, toxins, and circulating tumor cells. Moreover, they also mediate liver injury by interacting with cytokines such as IFN-γ and TNF-α (103). Mouse liver Kupffer cells are stimulated by bacterial superantigens to synthesize IL-12 and IL-18, which activate NK cells and NK1+ T cells to produce IFN-g (104). IL-12/LPS-activated NK1 T cells exhibited potent cytotoxicity against homologous liver cell lines in vitro ( 105). Originating from the bone marrow (BM), NK cells are released into the circulation and are abundant in the spleen and liver (106). S1PR5 is a key chemokine receptor in NK cells that regulates the distribution of NK cells in vivo and their trafficking to lesion sites (107). In mice deficient in this receptor, NK cell distribution is altered, with decreased NK cell numbers in the blood and spleen and increased NK cell numbers in the lymph nodes (LN) and BM (108). Noteworthily, S1PR5 knockdown has been shown to reduce the number of circulating NK cells in the liver, spleen, and lungs of mice (109). S1PR5 is required for NK cell mobilization to inflammatory organs (108). Poly (I: C) is a compound that stimulates NK cells and induces the recruitment of NK cells from the spleen to the liver. After treatment with poly (I: C), wild-type NK cells accumulated in the liver (four to five-fold increase) and decreased in the spleen. At the same time, serum ALT/AST levels were marginally elevated, accompanied by mild inflammation and focal necrosis in the liver. In contrast, poly (I:C) treatment failed to cause significant changes in NK cell abundance in spleen or liver of S1PR5-deficient mice (110). PolyI: C induction also significantly up-regulated the expression of S1PR5 in the liver (111). Dong et al. demonstrated that the depletion of NK cells significantly attenuated PolyI: C-induced liver injury (112). Overall, these findings indicate that modulating the distribution of NK cells in the liver by regulating the expression of S1PR5 may be a new therapeutic approach for the treatment of sepsis-induced liver injury.

Bile formation is an active osmotic process that involves the passive movement of organic and inorganic molecules across the tubular membrane and water and also necessitates the involvement of integrated membrane proteins, namely the intact cytoskeleton, tight junctions, and intracellular signaling (88). Bile acids are synthesized from cholesterol in hepatocytes and, after binding to glycine or taurine, are actively transported into the biliary system via ATP-binding cassette (ABC) transporters (113). Likewise, S1P can also be transported to the extracellular space by ATP-binding cassette (ABC) transporters (114). Hepatocytes secrete bile acids through bile salt export proteins (BSEP, ABCB11), ABCB4, and ABCG5/ABCG8 (115). An increasing number of in vitro studies have unveiled that LPS-induced proinflammatory mediators (including TNF-α) impair the downstream expression and functional integrity of hepatocyte transporters, such as BSEP and multidrug resistance-associated protein 2 (mrp-2) (116). Among them, the most prominent transport is the energy-dependent tubular ATP-binding cassette (ABC) transporter required for normal bile secretion, which underlies sepsis-associated cholestasis (117). This inflammatory shock may lead to permanent hepatic excretory dysfunction (85). ABCA1 and ABCG1 play a central role in cholesterol efflux from macrophages during atherosclerosis (118). In an earlier study, S1P and S1PR3 receptors were identified as modulators of ABCA1-mediated cholesterol efflux (118). The fact that S1PR3-deficient macrophages have lower ABCA1 gene expression and reduced cholesterol efflux suggests that sustained S1PR3 signaling is required to maintain basal cholesterol efflux (119). This finding led us to hypothesize the role of S1P and S1PR in the regulation of bile acid secretion in hepatocytes.

In sepsis, inflammatory factors may mediate sepsis-related excretory liver dysfunction through the PI3K pathway (85). Considering that bile acid-induced inflammasome activation has a synergistic effect with LPS, cholestasis further aggravates LPS-induced sepsis (120). It has also been found that in inflammatory cholangiopathies, proinflammatory cytokines stimulate biliary epithelium to produce NO through inducible nitric oxide synthase (NOS2) induction. In turn, NO causes ductal cholestasis through reactive nitrogen oxides (RNOS)-mediated inhibition of adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP)-dependent HCO3- and Cl- secretory mechanisms (116, 121). The use of JTE-013, a specific inhibitor of S1PR2, may improve cholestatic liver injury induced by common bile duct ligation by reducing hepatitis response and apoptosis (122). Nonetheless, the mechanism by which JTE-013 ameliorates liver injury remains elusive, and its relationship with the PI3K pathway and NO warrants further exploration.

Ascribed to anatomical connections, the theory of hepato-enteric circulation is widely accepted, whereby the gut and liver communicate bi-directly through the biliary tract, portal vein, and systemic circulation (123). At present, existing evidence suggests that the enterohepatic crosstalk between the gut and the liver through bacterial translocation and liver-derived molecules, such as bile acids, play a crucial role in the pathogenesis of sepsis (123). Due to bacterial invasion during sepsis, intestinal barrier disruption and intestinal microbiota dysregulation result in the translocation of intestinal pathogen-associated molecular patterns (PAMP) and damage-associated molecular patterns (DAMP) to the liver and systemic circulation (9). Under physiological conditions, the liver regulates immune defense through mechanisms such as bacterial clearance, cytokine production, acute-phase protein release, and regulation of inflammatory metabolism (124). However, during systemic infections, these inflammatory responses may become excessive, leading to impaired pathogen clearance and impaired hepatic metabolism, which can lead to further damage to the gut barrier (89).

The gut barrier consists of a single-cell layer of epithelium, the local immune system, and the microbiome (125). This barrier includes a mechanical component, namely the biological structure composed of intestinal epithelial cells (IEC) and vascular endothelial cells (EC) (126). Various tight junctions (TJS) are present between cells, which comprise various tight junction proteins and cadherins, such as including ZO-1, occludin, cadherin, claudin, and β-catenin. These junctions can resist the invasion of pathogens and harmful substances from infiltrating the intestinal mucosa and prevent the exudation of substances in the intercellular space (127). From the pathophysiology of intestinal injury, cellular alterations and bacterial toxins can induce intestinal edema and intestinal dysfunction by disrupting normal intercellular junctions, reducing vascular endothelial cadherins and TJS, and increasing vascular permeability (128). In preclinical models of sepsis, changes in tight junctions were observed after 1 hour of sepsis onset, with intestinal hyperpermeability persisting for at least 48 hours (125). LPS, a component of the outer wall of Gram-negative bacteria, alters TJ protein assembly, leading to small intestinal leakage, and regulates the inflammatory response through TLR4, further aggravating the changes in TJ (129).

S1P has been described as a barrier-enhancing molecule (130). In a clinical study, plasma S1P levels were reduced, and VE-cadherin levels were increased in patients with septic shock (22). S1P can up-regulate the expression of cell junction-related proteins such as E-cadherin and ZO-1 and promote VE-cadherin translocation, thereby strengthening the intestinal epithelial barrier and reducing the permeability of the intestinal epithelial layer, reducing sepsis-related intestinal injury, and improving the survival rate in sepsis (131, 132). In addition, a significantly negative correlation was noted between the severity of endothelial dysfunction and plasma S1P concentration in sepsis (133). Recent studies have hypothesized that S1P regulates EC biology via various molecular mechanisms, including vascular development and angiogenesis, inflammation, permeability, and the production of reactive oxygen species (ROS), nitric oxide (NO), and hydrogen sulfide (H₂S) (134). During sepsis, S1P interacts with the receptors S1PR1 on EC to reduce vascular permeability and maintain the EC barrier through the aforementioned mechanisms (135). Therefore, we posit that S1P plays a major role in intestinal barrier injury during sepsis. In an earlier study investigating alcoholic liver disease, treatment with citrate-ethanol-derived red rice seed skin extract (RRA) increased SPHK2 and S1P levels, improved gut microbiota composition, restored the integrity of the intestinal barrier, reduced plasma and liver LPS levels, and inhibited the activation of the Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway, as well as alleviated liver pathological damage and oxidative stress, reduced inflammation and apoptosis, and enhanced liver function (136). Consequently, alleviating damage to the intestinal barrier function may attenuate hepatic injury ( Figure 2 ). However, not all S1P receptors contribute to barrier enhancement (137). For example, intravascular administration of S1P can prevent inflammatory damage associated with acute lung injury. Conversely, elevated S1P concentrations in vitro may lead to severe disruption of the endothelial cell barrier, potentially through engagement of S1PRs other than S1PR1 (137).