New insights into the crosstalk between endocannabinoids and sphingosine-1-phosphate

Article type: Review Article

Keywords: endocannabinoids, anandamide, 2-arachidonoylglycerol, sphingosine-1-phosphate, cannabidiol, crosstalk, GPCRs, TRPV1, PPARγ

Authors: Cinzia Rapino, Sara Standoli, Francesca Cencetti, Paola Bruni, Sergio Oddi, Mauro Maccarrone

Affiliations: Department of Veterinary Medicine, University of Teramo, Teramo, Italy; Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy; Laboratory of Lipid Neurochemistry, European Center for Brain Research, IRCCS Santa Lucia Foundation of Rome, Rome, Italy; Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy

License: © 2025 The Authors CC BY 4.0 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Article links: DOI: 10.1016/j.jbc.2025.110781  |  PubMed: 41033556  |  PMC: PMC12597274

Relevance: Moderate: mentioned 3+ times in text

Full text: PDF (7.0 MB)

Bioactive lipids: Endocannabinoids versus sphingosine-1-phosphate

Bioactive lipids—particularly endocannabinoids (eCBs) and sphingosine-1-phosphate (S1P)—act as cellular messengers with highly dynamic transport and trafficking mechanisms that drive their signaling activity (ref. 1, ref. 2). The major eCBs are anandamide (N-arachidonoylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG), which possess multiple biological functions (ref. 1, ref. 3, ref. 4). AEA and 2-AG are, respectively, an N-acylethanolamine (NAE) and a glycerol ester formed through condensation with the carboxylic group of arachidonic acid (AA) (ref. 5, ref. 6). Both eCBs serve as key homeostatic regulators throughout the body and play vital roles in numerous physiological functions, such as brain development, cell survival, neurotransmission, pain sensation, immune response, energy homeostasis, bone metabolism, and vascular tone, just to list a few (ref. 1, ref. 7).

S1P is an important bioactive sphingolipid with a distinctive molecular structure typically characterized by an 18-carbon sphingosine backbone and a phosphate group esterified to the first hydroxyl position (ref. 8, ref. 9). However, the sphingoid base chain length can vary significantly, ranging from 12 to 22 carbons (ref. 10). S1P is present in biological fluids and is locally produced by most cell types and tissues, with particular relevance in the central nervous system (CNS), immune system, and vascular system (ref. 11).

Despite their different origins, eCBs and S1P share key molecular features. Indeed, they are both primarily produced “on demand” upon specific cellular stimuli (ref. 12, ref. 13); in addition, eCBs—but not S1P—can also be stored in cytosolic organelles such as adiposomes (ref. 14, ref. 15). Both eCBs and S1P require specific carriers for transmembrane transport (in and out) and trafficking (ref. 1, ref. 16, ref. 17) and usually act as local mediators with short-range paracrine action because of rapid degradation by specific enzymes (ref. 1, ref. 16, ref. 17). Furthermore, eCBs and S1P are ligands at different G-protein–coupled receptors (GPCRs) (ref. 18, ref. 19) with putative crosstalk capabilities (ref. 20, ref. 21, ref. 22).

In this review, we will critically discuss the points of contact and intersection between eCBs and S1P signaling, at the molecular and functional levels.

A common strategy of metabolic enzymes, receptors, and transporters

The metabolic routes of eCBs and S1P reveal intriguing commonalities, despite the distinct chemical nature of these lipids. The endogenous levels of both classes are tightly controlled by distinct biosynthetic and catabolic enzymes, which in the case of AEA and 2-AG lead to different in vivo concentrations (higher for 2-AG than for AEA), and hence to distinct receptor activation and signaling thereof (ref. 23).

The biosynthesis of AEA and 2-AG occurs mainly through the action of N-acyl-phosphatidylethanolamine–specific phospholipase D (NAPE-PLD) (ref. 24) and diacylglycerol lipase α and β isoforms (ref. 25, ref. 26, ref. 27), respectively. However, studies performed in NAPE-PLD knockout mice have revealed additional pathways (ref. 28), with an apparent redundancy that warrants AEA production even when the primary NAPE-PLD–dependent pathway is compromised.

AEA is primarily degraded by fatty acid amide hydrolase (FAAH) into AA and ethanolamine (EtNH₂) (ref. 29), whereas 2-AG is metabolized by monoacylglycerol lipase (MAGL) into AA and glycerol (ref. 30). Alternatively, AEA can undergo oxygenation via cyclooxygenase-2 (COX-2), forming prostaglandin-H₂-EtNH₂ (ref. 31, ref. 32), or it can be transformed by lipoxygenase (LOX) isozymes—5-LOX, 12-LOX, and 15-LOX—into hosphor derivatives like 11-HETE-EA, 12-HETE-EA, and 15-HETE-EA, respectively (ref. 33, ref. 34). Finally, cytochrome P450 (CYP) enzymes can epoxygenate AEA to form epoxyeicosatrienoyl-ethanolamide (ref. 35, ref. 36).

Much alike AEA, 2-AG can be oxygenated by COX-2, leading to PG-glycerol (ref. 37, ref. 38) and by LOX isozymes that form hosphor derivatives such as 12-HETE-G, 15-HETE-G, and eoxin derivatives (ref. 39, ref. 40, ref. 41). Epoxygenation of 2-AG by CYP at various positions results in different epoxyeicosatrienoyl-glycerols (ref. 42, ref. 43). These oxidative pathways represent critical control points for eCB signaling duration and can lead to new metabolites endowed with their own biological activity (ref. 44).

As for S1P, it is synthesized by ATP-dependent phosphorylation of sphingosine, catalyzed by sphingosine kinases 1 (SphK1) and 2 (SphK2), which have distinct subcellular localizations: SphK1 is primarily in the cytoplasm and cell membranes, whereas SphK2 is present mainly in mitochondria, nucleus, and endoplasmic reticulum (ref. 45, ref. 46, ref. 47). The SphK substrate sphingosine is, in turn, produced by ceramide hydrolysis driven by ceramidases (ref. 48). The catabolic pathways of cellular S1P involve S1P phosphatase–dependent dephosphorylation and irreversible cleavage into hexadecenal and EtNH₂ phosphate via S1P lyase, which represents the only exit point for sphingolipid degradation (ref. 49). Extracellular S1P can also be degraded by lysophospholipid phosphatase 3 into sphingosine, which can then be taken up by cells for further metabolism (ref. 50).

Both eCBs and S1P primarily signal through distinct families of GPCRs. In particular, AEA and 2-AG target cannabinoid receptors 1 and 2 (CB₁ and CB₂), whereas S1P activates five distinct receptors (S1PR_1–5) with both systems exhibiting overlapping anatomical distributions in the CNS and peripheral tissues (ref. 51, ref. 52, ref. 53, ref. 54). In addition to canonical CB₁ and CB₂ receptors, eCBs can bind to other GPCRs like GPR55, as well as non-GPCRs such as transient receptor potential vanilloid-1 (TRPV1) channel and nuclear peroxisome proliferator–activated receptors (PPARs) α, γ, and δ (ref. 20, ref. 55, ref. 56).

The biological activity of eCBs and S1P—both acting as intracellular messengers and extracellular agonists—is subjected to spatiotemporal regulation, which is tightly dependent on metabolic enzymes and transport/trafficking mechanisms (ref. 14, ref. 57, ref. 58, ref. 59). For instance, in the case of S1P, its metabolism is finely regulated by diverse stimuli, including growth factors, cytokines, hormones, and neurotransmitters (ref. 57, ref. 59), and the tissue-specific expression of S1P_1–5 receptors contributes to the selectivity of intracellular signaling pathways triggered thereof (ref. 60). Much alike eCBs (ref. 61, ref. 62), the rapid metabolism of S1P is critical to maintain its endogenous tone and hence signaling pathways.

Of note, S1P is not the only bioactive sphingolipid. Indeed, ceramide—considered the central hub of the sphingolipid pathway—has opposite effects compared with S1P: it induces apoptosis, whereas S1P promotes cell survival and proliferation (ref. 63). Remarkably, ceramide metabolism is closely interconnected with that of S1P and is regarded as the “sphingolipid rheostat” that determines cell fate (ref. 64). Due to its polar nature, intracellularly produced S1P must flip to the outer layer of plasma membrane in order to interact with its receptors (the so-called inside–out signaling) or to be released into the bloodstream (ref. 65). In this context, it should be recalled that S1P levels significantly vary between different body districts and may be altered under disease conditions (ref. 11).

Although eCBs and S1P are primarily produced inside the cell and then exported outside in response to various stimuli, emerging evidence demonstrates that both lipids can also be packaged into and transported by extracellular vesicles (Evs) (ref. 66, ref. 67). Indeed, Evs serve as carriers that protect these hydrophobic signals from degradation and facilitate their transport across aqueous environments to distant cellular targets. The packaging of eCBs in microvesicles has been demonstrated in microglial cells, where AEA localizes on vesicle surfaces and remains biologically active, that is, capable of binding to and activating presynaptic CB₁ receptors to modulate synaptic transmission (ref. 66, ref. 68). Similarly, S1P—and in some cases even its biosynthetic enzymes—have been detected within Evs released from various cell types, such as hepatocarcinoma cells, endothelial cells, and pancreatic β-cells (ref. 67, ref. 69, ref. 70, ref. 71). The vesicular transport of eCBs and S1P not only extends their signaling range beyond the production sites but also provides a mechanism that enables navigation of these lipids through aqueous extracellular environments to reach their ultimate targets.

Further details of eCB and S1P systems—including metabolic enzymes, receptors, transporters, and trafficking mechanisms—are summarized in Box 1 and Box 2, respectively (Figs. 1 and 2).

Crosstalk between eCBs and S1P

Crosscommunication between eCB and S1P systems occurs through multiple mechanisms: (i) receptor heterodimerization and coregulation, (ii) mutual metabolic modulation, and (iii) integrated regulation of downstream effectors.

Heterodimerization and coregulation

Heterodimerization (i.e., the formation of a complex between two different receptor partners) and coregulation of distinct receptors play crucial roles in intracellular signaling (ref. 72, ref. 73), with a particular impact on the interaction between S1P-binding and eCB-binding receptors, and hence on energy homeostasis, cancer progression, and pain modulation.

The interaction between CB₂ and S1P₅ receptors forms a regulatory checkpoint that limits tumor progression in glioblastoma cells, as revealed by bioluminescence resonance energy transfer analysis (ref. 73). Confocal microscopy confirmed colocalization and cointernalization into the cytoplasm upon agonist stimulation. Moreover, CB₂ upregulated tumor progression genes like Ki67 and p21, but S1P₅ costimulation attenuated these effects by 60% to 70%. Such a CB₂–S1P₅ receptor heterodimerization expands the functional diversity of both lipid signaling systems, enabling context-dependent modulation of cellular responses (ref. 72, ref. 73). The heterodimerization of S1P₅ with GPR55 represents another regulatory checkpoint that balances protumorigenic and antitumorigenic signals. Indeed, GPR55 and S1P₅ form a heterodimer in colon cancer cells, which involves the transmembrane segments of S1P₅ with a minimal contribution from its C-terminal region, as demonstrated by bioluminescence resonance energy transfer experiments (ref. 72). When activated independently, each receptor promotes extracellular signal–regulated kinase phosphorylation, upregulation of protumorigenic genes ATF3, HIF-1α, and Sp1, and thus colon cancer cell proliferation. Instead, simultaneous stimulation of both receptors triggers cointernalization of the heterodimer, ultimately suppressing tumor progression (ref. 72).

An example of receptor coregulation is the ability of both S1P and eCBs to interact with PPARγ through distinct molecular mechanisms, thus influencing gene regulation and therapeutic outcomes (ref. 74, ref. 75). Parham et al. (ref. 75) showed that S1P directly interacts with PPARγ through its ligand-binding domain that involves histidine 323, as revealed by in silico docking and in vitro binding assays. At physiological concentrations, S1P stimulates recruitment of the PPARγ coactivator 1-β, leading to the formation of a transcriptional complex within endothelial cells (ref. 75). Accordingly, S1P activates PPARγ-dependent gene reporters, selectively modulating target genes by upregulating PPARγ coactivator 1-β and plasminogen activator inhibitor-1, while suppressing the expression of the scavenger receptor CD36. Importantly, the proangiogenic action of S1P, leading to in vitro tube formation, is PPARγ dependent and is blocked by PPARγ antagonists (ref. 75).

Notably, AEA and 2-AG can also bind directly to the ligand-binding domain of PPARγ, contributing to anti-inflammatory and neuroprotective effects (ref. 74). Moreover, 2-AG also interacts indirectly with PPARγ via its COX-2-generated metabolites (ref. 76). Further indirect mechanisms of eCB–S1P intersection include (i) PPARγ ligand (e.g., ciglitazone)-dependent inhibition of FAAH and subsequent increase of AEA levels that potentiate PPARγ activation (ref. 77) and (ii) synergistic effect of CB₁–CB₂ signaling with PPARγ pathways, to mediate neuroprotection and related metabolic effects (ref. 74, ref. 78, ref. 79).

Mutual metabolic modulation

Communication between the eCB and S1P systems also occurs through regulation of their metabolic enzymes. In rat carotid arteries, AEA induces relaxation through a mechanism that involves CB₂, which subsequently activates SphK1 to produce S1P. The latter, in turn, acts via S1P₃ receptor in the vascular endothelium to promote vasodilation (ref. 80). Similarly, the activation of SphK1, but not of SphK2, and the engagement of S1P₁ that is expressed at the level of vascular smooth muscle, is required for the reduction of systolic blood pressure exerted by AEA (ref. 81).

Moreover, in lipopolysaccharide (LPS)-stimulated BV2 microglia cells, transcriptional upregulation of both SphK1 and SphK2 is induced, contributing to increased production of proinflammatory cytokines like tumor necrosis factor α and interleukin-1β (ref. 22). In the same cells, inhibition of FAAH prevents LPS-induced SphK1 and SphK2 upregulation as well as cytokine production. In addition, activation of CB₂ by the synthetic agonist JWH133 mimics the anti-inflammatory effects of FAAH inhibition, positioning SphK1 and SphK2 at the intersection between proinflammatory LPS and anti-inflammatory eCB signaling pathways in microglia (ref. 22).

Also, LOX isozymes, which metabolize eCBs into oxylipin derivatives like hydroxyeicosatetraenoic acids (ref. 82), are modulated by S1P (ref. 83, ref. 84). For instance, S1P can reduce 5-LOX activity—particularly in immune cells like neutrophils and macrophages—through S1P₄ engagement (ref. 83). In general, it should be noted that regulation of AA metabolism by S1P likely affects eCB tone and biological activity. Although the eCB–S1P crosstalk via AA is complex and still under investigation, several mechanistic links support its potential in vivo relevance. S1P can influence intracellular AA mobilization by activating calcium-independent and calcium-dependent phospholipases A₂ (iPLA₂ and cPLA₂) (ref. 85). By inducing the expression of the AA dioxygenase COX-2, S1P triggers a metabolic competition that favors the fueling of prostaglandin production at the expense of eCB synthesis (ref. 86). Depending on the target tissue, such a switch of AA metabolism toward prostaglandins or eCBs may tip the balance between proinflammatory and anti-inflammatory effects or pronociceptive and antinociceptive effects (ref. 87). While direct experimental evidence linking S1P-mediated regulation of AA metabolism to changes in eCB levels is limited, the biochemical overlaps between S1P and eCB systems speak in favor of this hypothesis. Ongoing research in lipidomics and cell signaling has begun to uncover this intricate crosstalk, especially in contexts such as neurodegenerative diseases, cancer, chronic pain, and immune function (ref. 88, ref. 89, ref. 90).

A third mechanism of intersection between S1P and eCB signal transduction pathways involves the eCB-binding receptor TRPV1, which is also a key effector of S1P in several cellular contexts (ref. 91, ref. 92, ref. 93). In fact, S1P transactivates TRPV1 in primary sensory neurons to regulate nociception and pain. In particular, TRPV1 is coexpressed with S1P₃ receptors in subsets of nociceptors, where S1P₃ stimulation potentiates TRPV1 activity, overall leading to heat hypersensitivity and pain (ref. 91). Likewise, S1P-induced calcium influx in dorsal root ganglia neurons is partially abolished by TRPV1 antagonists, whereas in vivo studies show that TRPV1-knockout mice exhibit significantly reduced pain responses (e.g., wiping and thermal hyperalgesia) after S1P injection (ref. 92). At the mechanistic level, S1P enhances TRPV1-mediated thermal pain sensitivity via a rapid G_αi-coupled signaling pathway that involves PI3K, PKC, and p38 mitogen-activated protein kinase (MAPK) l (ref. 93).

Finally, in a recent study performed in murine C2C12 myoblasts, S1P treatment for 24 h significantly increased TRPV1 expression at both mRNA and protein levels, whereas reducing CB₂ protein levels. The opposite regulation of TRPV1 and CB₂ by S1P suggests a mechanism whereby S1P channels eCB signaling toward TRPV1-dependent pathways, which are critical for calcium influx and mitochondrial function (ref. 21). In the same C2C12 cells, TRPV1 activation by the stable AEA analog methanandamide (mAEA) increases mitochondrial membrane potential (ΔΨ_m) and upregulates PPARγ coactivator 1-α, a key regulator of mitochondrial biogenesis. Of note, treatment with S1P counteracts these effects of mAEA, likely through TRPV1 desensitization or altered calcium flux (ref. 21). The interplay between mAEA and S1P in C2C12 cells appears critical during myogenesis, where balanced mitochondrial activity is needed to ensure energy supply for cell differentiation.

A summary of the interactions between eCB and S1P at the structural and functional levels is shown in Figure 3.

Integrated regulation of downstream effectors

Crosscommunication between eCBs and S1P can also occur through the integrated regulation of downstream effectors triggered by the binding of eCBs and S1P to their receptor targets. Indeed, both lipid signaling systems modulate a variety of physiological processes via binding to G_i-, G_q-, and G_12/13-coupled receptors, which are coexpressed in specific body districts (i.e., CNS, immune, and vascular systems), thus allowing context-specific integration of signals. As a consequence, the cooperative modulation of effectors, like ion channels, protein kinases, and nuclear transcription factors, may have important implications in physiological and pathological processes.

Both eCB and S1P systems regulate common effectors that drive distinct signal transduction pathways, such as adenylyl cyclase, MAPK/extracellular signal–regulated kinase, PI3K/Akt, and Rho/ROCK (Rho-associated protein kinase). The crosstalk between eCBs and S1P can reinforce or weaken a specific pathway of signal transduction in both the CNS and peripheral tissues, as schematically summarized in Table 1.

Cannabidiol: A link between eCBs and S1P

Among the numerous constituents of cannabis (Cannabis sativa) preparations that interact with the eCB system, cannabidiol (CBD) has emerged as one of the most intriguing compounds for its therapeutic potential (ref. 94). The (+)-enantiomer of CBD, unlike its (−)-counterpart, has been shown to potently activate S1P₁ and S1P₃ receptors, thereby reducing cAMP levels in a G_i-dependent manner (ref. 95). This effect was blocked by both dual and selective S1P₁ and S1P₃ antagonists, confirming the potential of (+)-CBD for the treatment of neurological disorders via S1P signaling (ref. 95). Notably, (+)-CBD also binds to CB₁ as an inverse agonist (ref. 96, ref. 97, ref. 98), whereas (−)-CBD acts as a negative allosteric modulator of the same receptor and reduces the efficacy and potency of Δ⁹-tetrahydrocannabinol—the main psychoactive ingredient of cannabis—and AEA at CB₁ (ref. 99). Moreover, CBD acts as a full agonist at TRPV1 channels (ref. 100), and with lower potency at CB₂ (ref. 101) and PPARγ (ref. 102), thereby influencing anxiety, epilepsy, neuropathic pain, and inflammation (ref. 103).

In addition to eCBs—and S1P-binding receptors—CBD also modulates the metabolic enzymes of these lipids. Indeed, CBD is a potent inhibitor of FAAH, thus increasing cellular levels and signaling activity of AEA (ref. 104). CBD also modulates 2-AG metabolism by inhibiting MAGL and the other 2-AG hydrolases, ABHD6 and ABHD12 (ref. 105). In parallel, CBD influences sphingolipid metabolism by increasing S1P levels while reducing ceramide accumulation. The latter effect clearly shifts the ceramide–S1P rheostat toward cell survival and improved insulin sensitivity in the CNS (ref. 106, ref. 107), as well as in peripheral tissues like skeletal muscles, where it ameliorates glucose metabolism (ref. 103, ref. 106). Incidentally, another cannabis ingredient, cannabigerol, when administered in a rat model of high-fat–induced insulin resistance, increases ceramide conversion to S1P, potentially improving insulin sensitivity and providing protection from liver steatosis (ref. 108).

CBD has been shown to inhibit several CYP enzymes, particularly CYP2J2, which metabolizes eCBs into bioactive epoxyeicosatrienoic acids (ref. 109). This metabolic interference creates a complex pharmacological profile, whereby CBD not only enhances eCB tone but also redirects eCB metabolism toward alternative pathways that may influence the sphingolipid system, in particular through production of common precursors like AA.

The intersection of CBD and S1P signaling can also occur at the level of LOX isozymes, which represents an emerging and particularly fascinating area of bioactive lipid crossregulation. In fact, allosteric modulation of 5-LOX by CBD can shift its enzymatic activity from producing proinflammatory leukotrienes to generating anti-inflammatory specialized proresolving mediators (ref. 110). In line with this, S1P negatively modulates 5-LOX activity and reduces leukotriene biosynthesis to exert potent anti-inflammatory effects (ref. 83). Moreover, CBD strongly induces the formation of specialized proresolving mediators and 12/15-LOX products in resting cells by stimulating cPLA₂-dependent release of polyunsaturated fatty acids as well as through allosteric activation of 15-LOX (ref. 110). In addition, S1P upregulates 15-LOX expression through a complex molecular pathway that engages activation of S1P₁ and S1P₃ receptors in macrophages, contributing to immunosuppressive tumor microenvironments (ref. 84). Overall, the intersections between CBD, S1P, and eCBs hold a promising therapeutic potential—as yet poorly explored—for the treatment of inflammatory conditions through their convergent effects on the production of bioactive lipids.

A summary of the interactions between CBD, eCBs, and S1P at the structural and functional levels is shown in Figure 4.

Conclusions

This review has highlighted how eCBs and S1P represent two complex signaling networks that, beyond canonical GPCR activation, can mutually influence metabolism, transport, trafficking, and transcription factor activity of each other. Both systems interact through multiple coregulatory mechanisms, such as receptor heterodimerization and coregulation (e.g., S1P₅, CB₂, GPR55, PPARγ), shared metabolic enzymes (e.g., SphK1–2, LOXs), and integrated downstream effectors, particularly of TRPV1, as summarized in Figure 5. This interplay results in finely tuned, context-dependent modulation of bioactive lipids in cellular responses, with an impact on the regulation of inflammation, vascular function, neuronal activity, and insulin sensitivity.

Furthermore, the cannabis ingredient CBD demonstrates significant potential as a modulator of eCB and S1P endogenous systems. By modulating dioxygenase enzymes that metabolize eCBs and S1P—such as LOX, COX, and CYP isoforms—CBD further underscores the biochemical convergence of their pathways. Therefore, the activity of these enzymes represents a metabolic “checkpoint,” where the outputs of eCB and S1P signaling, along with those of CBD, are integrated and finely tuned.

On a final note, recent studies have revealed novel mechanisms of crosscommunication between bioactive lipid systems. In fact, an intriguing discovery has shown that the nuclear translocation of a truncated form of S1P₂ induces PPARα degradation, which, as a consequence, blocks transcription of lipid catabolic genes (ref. 111). Moreover, a novel regulatory role of NAPE-PLD as an unexpected target of thiazide diuretics has been recently reported, pointing at it as a moonlighting enzyme (ref. 112). These findings further support the notion that our current understanding of lipid signaling is still in its infancy, and so far, only the tip of the iceberg has been scratched.

In conclusion, it seems apparent that eCB and S1P signaling pathways operate through interconnected networks of remarkable complexity. As yet, the biochemical crosstalk between these bioactive lipids remains incompletely understood, potentially limiting the therapeutic exploitation of these signals. Future strategies targeting the spatiotemporal dynamics of lipid transport—from intracellular trafficking to extracellular distribution—combined with selective receptor engagement may unlock novel therapeutic opportunities that current approaches have not fully realized.

Conflict of interest

The authors declare that they have no conflicts of interest with the contents of this article.

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