Article

ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 5, pp. 658-675 © Pleiades Publishing, Ltd., 2026.

658

REVIEW

Sphingosine-1-Phosphate Is a Key Signaling Molecule

in Normal Conditions and in Multiple Sclerosis

Dmitry A. Ganin

1,a

* and Mariya N. Zakharova

Russian Center of Neurology and Neurosciences, 125357 Moscow, Russia

e-mail: ganin.d.a@neurology.ru

Received January 20, 2026

Revised April 13, 2026

Accepted April 14, 2026

Abstract— Sphingosine-1-phosphate (S1P) is one of the most extensively studied bioactive signaling molecules

of sphingolipid metabolism, which plays a pivotal role in regulating numerous processes in the central ner-

vous system and immune system. Acting as an extracellular ligand for five subtypes of G-protein-coupled

receptors (S1PR

-S1PR

) as well as an intracellular metabolic mediator, S1P controls lymphocyte migration,

blood-brain barrier permeability, survival and differentiation of oligodendrocytes, reactivity of astrocytes

and microglia, and balance between inflammation, neurodegeneration, and neuroprotection. In pathogen-

esis of the demyelinative diseases, particularly multiple sclerosis, disruption of the “sphingolipid rheostat”

is observed – a shift toward predominance of pro-apoptotic ceramides and relative decrease in the S1P

levels, which promotes prevalence of the neuroinflammatory and neurodegenerative processes over remy-

elination. This review summarizes current data on the structure, metabolism, and intra- and extracellular

signaling pathways of S1P, its dual role under physiological conditions and in multiple sclerosis, and an-

alyzes approaches to pharmacological modulation of S1P signaling pathways, highlighting the prospects of

selective targeted therapy aimed at immunomodulation, neuroprotection, and stimulation of remyelination.

DOI: 10.1134/S0006297926600122

Keywords: sphingosine-1-phosphate, signaling molecule, sphingolipids, S1P receptors, myelin, demyelination,

remyelination, multiple sclerosis, neuroinflammation, S1P receptor modulators, sphingolipid rheostat

* To whom correspondence should be addressed.

ROLE OF SPHINGOLIPIDS

AND SPHINGOSINE-1-PHOSPHATE

AS STRUCTURAL AND SIGNALLING

COMPONENTS OF MYELIN

Demyelinative diseases of the central nervous sys-

tem (CNS) comprise a broad spectrum of neurological

disorders that lead to significant disability among the

young working-age population. According to the latest

data, published in 2024 as part of the joint project

between the Multiple Sclerosis International Federa-

tion and the World Health Organization, approximate-

ly 2.9 million people worldwide suffer from multiple

sclerosis (MS). It has been shown that the prevalence

of MS increased by 58% between 2013 and 2020  [1].

Analysis of epidemiological data allows us to predict

a further increase in prevalence and incidence ofMS.

Current trends highlight high relevance of demye-

linative diseases; in this context, the search for new

therapeutic targets that play a pivotal role in the im-

munopathogenesis of the disease attracts particular

interest. Molecules possessing signaling properties

and regulating a large number of metabolic pathways

are best suited to act as such targets, as they are ca-

pable of influencing multiple aspects of pathogenesis.

Demyelination is an autoimmune process involving

destruction of the myelin sheath – a multilayered

membrane structure formed by the spirally wrapped

plasma membranes of glial cells: oligodendrocytes in

the CNS and Schwann cells in the peripheral nervous

system (PNS). Each layer of the myelin sheath com-

prises two lipid bilayers separated by protein com-

ponents, with periodicity of approximately 12-18  nm,

which ensures its high electrical insulation  [2]. Un-

like other cell membranes, where the ratio of lipids

to proteins is approximately 1  :  1, the myelin sheath

S1P – KEY SIGNALING MOLECULE IN NORMAL CONDITIONS AND IN MS 659

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

is characterized by a unique biochemical composition:

70-85% consists of lipids and 15-30% of proteins, in-

cluding the myelin basic protein (MBP), proteolipid

protein (PLP), myelin protein zero (MPZ) etc. Relative

water content of the myelin sheath is approximate-

ly 40% of the total mass of myelin in  situ  [3]. Lipid

composition of myelin ensures stability and compact-

ness of the myelin sheath: cholesterol accounts for ap-

proximately 40-46% of all lipids, phospholipids – for

~40%, and glycolipids – for ~20%  [4]. The most signif-

icant biological role, of all the lipids studied to date,

is attributed to sphingolipids – a specialized class of

bioactive lipids that participate in formation of lipid

rafts – microdomains containing specific protein

components (receptors, ion channels and enzymes).

Sphingolipids are functionally defined as lipid mol-

ecules whose levels change in response to specific

stimuli; these lipids subsequently regulate specific

downstream effector molecules and targets. Thus, bio-

active lipids are components of signaling networks,

which fundamentally distinguishes them from other

lipids that perform primarily structural and/or ener-

gy functions [5, 6]. In recent years, a wealth of evi-

dence has accumulated regarding the involvement of

sphingolipid metabolites in pathogenesis of not only

autoimmune demyelinative diseases but also of neu-

rodegenerative disorders. Of particular interest in this

field is sphingosine-1-phosphate (S1P) – a biologically

active, multifunctional signaling molecule that plays

a key role in embryonic development, organ morpho-

genesis, maintenance of vascular integrity, regulation

of vascular tone, barrier function of endothelium, and

maintenance of immune homeostasis  [7]. S1P is char-

acterized by a dual signal transduction mechanism

as evidenced by its role in the interaction of neural

signals and metabolic pathways in both normal and

pathological conditions. S1P exerts its effects via two

main pathways: through the extracellular receptors

(S1P-R

-S1P-R

), which belong to the G-protein-coupled

receptor (GPCR) family, and through the intracellular

targets including regulation of enzymes, transcription

factors, and signaling cascades that influence metab-

olism, autophagy, apoptosis, and mitochondrial func-

tion  [7,  8]. The extracellular pathway mediates neu-

romodulation, regulation of neuroinflammation, cell

migration, and survival, as well as control of nerve

impulse transmission and synaptic plasticity. The in-

tracellular pathway allows S1P to directly influence

cellular metabolic processes, including the balance

between pro-apoptotic ceramide and neuroprotective

S1P, which is critical for maintaining homeostasis and

preventing neurodegeneration  [9].

Pharmacological modulation of S1P signaling has

already proven its efficacy, underscoring relevance of

this topic: a new class of drugs – sphingosine-1-phos-

phate receptor modulators (Fingolimod, Siponimod,

Ozanimod, Ponesimod, Etrasimod, etc.) has been de-

veloped, which are currently used to treat not only

relapsing but also progressive forms of MS  [10,  11].

Understanding of these mechanisms underlies mod-

ern personalized medicine, where S1P signaling path-

ways are becoming targets for predictive diagnostics,

monitoring, and development of new targeted drugs.

The aim of this review is to summarize information

on the structure, metabolic pathways, and physiologi-

cal functions of sphingolipids, in particular S1P, as sig-

naling molecules under normal conditions and in MS.

STRUCTURE OF SPHINGOSINE-1-

PHOSPHATE (S1P) AND SPHINGOLIPID

METABOLIC PATHWAYS

Sphingosine-1-phosphate (S1P) is a derivative of

sphingosine – an amino alcohol with a long 18-carbon

hydrophobic chain. Structurally sphingosine has one

amino group and two hydroxyl groups. Phosphory-

lation of sphingosine at the primary hydroxyl group

leads to formation of S1P  [12]. Due to the presence

of a hydrophobic “tail” and a polar phosphate “head”

the S1P molecule is able to embed itself in the lipid

bilayer of cell membranes, while simultaneously act-

ing as an extracellular signaling molecule. In particu-

lar, S1P is known as an important second messenger

that influences cell migration, angiogenesis, cell sur-

vival, and immune responses. A schematic molecular

framework of sphingolipids is shown in Fig.  1.

Detailed structures of known sphingolipids are

presented in Table  1.

Table  1. Composition of the R1- and R2-groups of

sphingolipids

Sphingolipids R1-group R2-group

Sphingosine-1-

phosphate

-PO

H- -H

Sphingosine -H -H

Ceramide -H fatty

acid

Sphingomyelin -PC/PE/PS fatty

acid

Cerebroside monosaccharide fatty

acid

Ganglioside oligosaccharide +

sialic acid

fatty

acid

Note. PC, phosphatidylcholine; PE, phosphatidylethanol-

amine; PS, phosphatidylserine.

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Fig. 1. Molecular backbone of sphingolipids: O-linked to a polar head group (R1) and amide-linked (–NH–) to a fatty acid (R2).

Biosynthesis of sphingolipids in the cell begins

with formation of ceramide  – a key intermediate in

sphingolipid metabolism. De  novo synthesis occurs

in endoplasmic reticulum: condensation of L-serine

with palmitoyl-CoA (catalyzed by the enzyme serine

palmitoyltransferase in the presence of pyridoxal

phosphate, NADPH and Mn

) leads to formation of

3-keto-dihydrosphingosine, which is next reduced to

dihydrosphingosine (sphinganine). Acylation of sphin-

ganine is catalyzed by the dihydroceramide synthase

to form dihydroceramide, while desaturation of dihy-

droceramide to ceramide is carried out by the dihy-

droceramide desaturase forming a double bond in the

sphingosine backbone  [13]. Ceramide is exported to

the Golgi apparatus with involvement of the ceramide

transporter protein (CERT)  [14], where the synthesis

of complex sphingolipids subsequently takes place –

sphingomyelins (with involvement of sphingomyelin

synthase) or glycosphingolipids (via reaction cata-

lyzed by glucosylceramide synthase). These complex

sphingolipids are further transported to the cell plas-

ma membrane, becoming part of its structure. In the

cell membrane, sphingolipids in combination with

cholesterol form specialized microdomains – lipid

rafts containing specific protein components (recep-

tors, ion channels and enzymes)  [12,  15].

Lipid–protein raft complexes play a role in facil-

itating membrane transport, signal transduction, and

formation of synaptic vesicles in presynaptic nerve

terminals [16]. In addition to the de  novo pathway,

an important source of S1P is a biochemical cas-

cade beginning with degradation of the membrane

sphingolipids: under the action of sphingomyelin-

ase sphingomyelin is hydrolyzed to ceramide and

phosphocholine. Ceramide could be further cleaved

by ceramidases forming sphingosine. The resulting

sphingosine is phosphorylated by the sphingosine ki-

nase (there are two isoenzymes: SphK1 and SphK2) to

form sphingosine-1-phosphate  [17]. This “sphingomye-

linase” pathway is activated in response to stress and

is thought to be involved in regulation of apoptosis

and other responses to damage.

Overall, the sphingolipid metabolic pathway can

be visualized as a “dimmer switch” between ceramide

and S1P. Ceramide and its associated metabolites typ-

ically initiate stress and pro-apoptotic responses (cell

cycle arrest, apoptosis), whereas S1P predominantly

triggers anti-apoptotic cascades and cell proliferation.

This balance has been termed the “sphingolipid rheo-

stat”  [2,  3] or the “rheostat of life and death”. Under

normal conditions, the “S1P-ceramide” ratio is strict-

ly regulated. However, in autoimmune demyelinative

diseases, particularly multiple sclerosis, disruption of

this balance is observed – involving a shift towards

ceramide accumulation and reduction in S1P levels,

which contributes to the predominance of cellular

processes of apoptosis and inflammation  [18]. The

available data on sphingolipid metabolism are pre-

sented in Fig. 2.

S1P is eliminated via both irreversible and re-

versible pathways. The S1P produced within the cell

could be metabolized via three main pathways: deg-

radation into metabolites (irreversible pathway), de-

phosphorylation back to sphingosine (reversible path-

way), or export into the extracellular space. The key

enzyme in S1P catabolism is sphingosine-1-phosphate

lyase (SPL), which irreversibly cleaves S1P into eth-

anolamine phosphate and palmitoyl aldehyde. This

reaction effectively removes sphingolipid from the

metabolic cycle and maintains low levels of S1P in

the tissues. Alternatively, S1P could be dephosphor-

ylated by the specific S1P phosphatases with revers-

ible formation of sphingosine. In the plasma mem-

brane and extracellular space S1P phosphatases (e.g.

LPP3) inactivate S1P, thereby helping to maintain the

sphingosine-1-phosphate concentration gradient. S1P

is exported via specific ABC transporters or trans-

porters of the major facilitator superfamily, which

“flip” the S1P molecule from the inner to the outer

leaflet of the plasma membrane, thereby enabling its

extracellular action in an autocrine manner (within

the same cell). The tissue-specific transporters such

as the SPNS2 (sphingolipid transporter-2) protein of

vascular endothelial cells and lymphatic endothelial

cells and MFSD2B (major facilitator superfamily do-

main-containing protein 2B) in erythrocytes facilitate

export of S1P resulting in formation of extracellular

gradients  [7,  13].

Under normal conditions, the main cellular

sources of S1P circulating in the blood are red blood

cells and vascular endothelial cells, whereas S1P in

the lymphatic fluid is produced by the lymphatic en-

dothelial cells  [19]. During inflammation excessive

S1P production is driven by activation of mast cells

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Fig. 2. Sphingolipid metabolic pathway.

and platelets  [20]. Since internal organs actively syn-

thesize and release S1P, and it is rapidly eliminated

in peripheral tissues, a marked S1P concentration

gradient is established within the body. In blood and

lymph, the S1P levels are high (S1P is constantly re-

leased from erythrocytes via the MFSD2B transport-

er and from vascular endothelium – via the SPNS2

transporter, and is also released by platelets). In con-

trast, the S1P concentration in interstitial fluid is very

low due to active degradation by the enzymes (SPL,

S1P phosphatases)  [7,  13]. The extracellular S1P gra-

dient (high concentration in the systemic circulation

and low in the tissues) has fundamental physiologi-

cal significance: it serves as a key signal for the exit

of immune cells from lymphoid organs. This process

limits the concentration of S1P both inside and out-

side the cell, thereby indirectly regulating subsequent

signaling pathways. A generalized representation

of the process of S1P gradient formation is shown

in Fig.  3.

A number of studies have shown that the im-

paired function of S1P transporters leads not only to

the developmental defects but also to the early-onset

hearing loss  [21] as well as to retinal damage  [22].

These observations suggest that the spatial S1P signal-

ing, which is critical for embryogenesis and postnatal

physiological processes, leads to the development of

pathological conditions when dysregulated. Cellular

mechanisms by which activity of the S1P transport-

ers is regulated remain poorly understood at present.

Approaches aimed at restoring normal transporter

function may prove promising in the treatment of

various diseases in which extracellular S1P gradients

are disrupted.

Further activation of the S1P-receptor (S1P-R)

occurs through binding to the chaperone proteins,

which ensures its solubility in an aqueous environ-

ment [7, 23]. The S1P chaperone proteins, which bind

S1P tightly and transport it in the blood and intersti-

tial fluids, facilitate activation of the S1P receptors on

the target cells. S1P is transported in the bloodstream

by the chaperone proteins: a component of high-den-

sity lipoproteins (HDL) – apolipoprotein  M (ApoM)

and serum albumin; S1P is presented to S1P-Rs in

this form. Most of the S1P molecules in blood are

bound to ApoM-HDL, which performs several func-

tions: it maintains stable S1P level in the blood plas-

ma for several hours  [24] preventing its degradation

and enhances its interaction with receptors. In con-

trast, the S1P molecules bound to albumin have a

short half-life in plasma (a few minutes) and activate

the S1P-Rs differently from the ApoM-HDL-bound S1P

as they have lower affinity  [25]. The S1P molecules

bound to ApoM-HDL in haematopoietic stem cells

suppress lymphopoiesis via the S1P-S1P-R

signaling

pathway  [26]. Furthermore, the ApoM-bound S1P sup-

presses the cytokine-induced inflammatory responses

in endothelial cells, thereby maintaining vascular in-

tegrity  [27]. It possesses biased agonist activity, i.e.,

it selectively induces specific biological responses.

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Fig.  3. Formation of the S1P gradient. VEC, vascular endothelial cells. LEC, lymphatic endothelial cells. HDL (ApoM), high-den-

sity lipoprotein-associated apolipoprotein M.

Other HDL-associated factors such as apolipoprotein

A1 and cellular HDL receptor (scavenger receptor-B1),

as well as ability of HDL to modulate organization of

the receptor-effector complexes in the lipid rafts are

likely also involved in formation of the biased signal-

ing [28,  29]. Furthermore, relative stability of the S1P

bound to ApoM-HDL compared with the S1P bound to

serum albumin may play a role in the different kinet-

ics of receptor activation and signal transduction [30].

S1P-RECEPTORS: STRUCTURE, FUNCTIONS,

AND INTRACELLULAR SIGNALLING PATHWAYS

To date, five subtypes of S1P-receptors have been

identified: S1P-R

, S1P-R

, and S1P-R

All belong to the superfamily of G-protein-coupled

receptors that are embedded in the cell membrane

and share a similar structure – a seven-transmem-

brane domain linked to a G-protein on the cytoplas-

mic side  [31].

Activation of the S1P-receptors by circulating S1P

bound to the chaperone proteins is accompanied by

the reduction in their surface expression on the cell

surface  [32] with the result that the vascular and

haematopoietic cells, which are under constant ex-

posure to circulating S1P, become refractory to fur-

ther stimulation. The S1P-R

endocytosis is controlled

by the G-protein-coupled receptor kinase  2 (GRK2),

dynamin, and moesin  [33]. Loss of these regulatory

mechanisms of S1P-R

leads to alterations in biolog-

ical effects including impaired immune cell migra-

tion and dysfunction of the vascular endothelial bar-

rier  [34,  35].

Development of the S1P-R

reporter mouse lines

revealed existence of the plasma S1P-dependent ac-

tivation of β-arrestin in the vascular endothelium

during systemic endotoxemia as well as in the aortic

endothelium in the areas of impaired blood flow  [36].

The results of these studies indicate that the S1P-R

expression is downregulated in the damaged endothe-

lial cells. Internalization of S1P-R

ultimately leads to

its proteasomal degradation via the ubiquitin ligase

enzyme WWP2 (WW Domain Containing E3 Ubiquitin

Protein Ligase  2)  [37]. The ability to monitor the S1P

receptor function in  vivo in real time is expected to

lead to new insights into the physiological regulation

of S1P signaling and its dysregulation in various dis-

eases [7,  36]. Activity of the S1P receptors in addition

to their primary ligand – sphingosine-1-phosphate – is

also modulated by other molecules as well as co-recep-

tors: for example, in the development of cholestasis,

the elevated levels of conjugated bile acids activate

S1P-R

, which may play a role in the pathogenesis of

liver fibrosis in cholestasis  [38]. In endothelial cells,

the activated protein C receptor and the hyaluron-

ic acid receptor CD44 transactivate S1P-R

enhancing

the barrier function, thereby preventing plasma leak-

age and limiting inflammatory responses  [39].

In lymphocytes, the activation-induced CD69

binds to S1P-R

and reduces its expression  [40],

which is critical for regulating exit of lymphocytes

from the lymphoid organs and their tissue residency.

In the CNS, binding of the extracellular domain of

NOGOA (a neuronal repulsive signaling molecule reg-

ulating formation of neural networks) to S1P-R

in-

duces signaling via the GPCR-dependent Gα13–RhoA

pathway inhibiting neurite growth, thereby ensuring

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Table  2. Expression and functional roles of sphingosine-1-phosphate receptors (S1P-R

-S1P-R

) in different

tissues

Receptor Tissue expression pattern Key physiological functions

S1P-R

basically, all tissues in the body; vascular

endothelium, smooth muscle cells,

T andB lymphocytes, neurons, astrocytes,

oligodendrocytes

maintenance of vascular integrity (Akt/eNOS

pathway), regulation of blood-brain barrier

permeability, control of lymphocyte efflux

from lymph nodes, involvement in neurogenesis

and neuronal survival

S1P-R

vascular endothelium, smooth muscle cells,

neurons, microglia, monocytes, specific

populations of lymphocytes

activation of the Rho/ROCK cascade, stabilization

of intercellular junctions, inhibition of cell

migration, reduced neuronal excitability

S1P-R

heart, blood vessels, astrocytes, microglia vasoconstriction, regulation of heart rate,

activation of Rho and intracellular Ca

stimulation of astrogliosis and cytokine

production

S1P-R

thymus, spleen, lymph nodes, lungs, bone

marrow, cells of the immune system (NK-cells,

T- and B-lymphocytes)

regulation of immune cell migration and

differentiation, control of the cytokine response,

involvement in innate immunity

S1P-R

spleen, oligodendrocytes and oligodendrocyte

precursor cells, hippocampal neurons, astrocytes,

NK-cells

maintaining survival and differentiation

of oligodendrocytes, regulation of myelination,

contributing to the barrier function

of endothelium

synaptic plasticity in the hippocampus and motor

cortex  [41]. The examples cited above demonstrate

that the S1P-receptors interact with a multitude of

other signaling pathways. Mechanistic details of the

S1P transfer from the chaperone proteins to S1P-re-

ceptors, actions of the various receptor-modulating

molecules, and roles of the regulated endocytosis and

retention of S1P receptors in the plasma membrane

require further investigation.

As noted above, the S1P-receptors belong to the

superfamily of G-protein-coupled receptors. Differenc-

es in amino acid sequence result in varying specific-

ity of binding to Gα-subunits and, consequently, acti-

vation of different intracellular signaling pathways.

S1P-R

highly selectively activates the G

protein.

Upon binding of S1P to S1P-R

, GTP is exchanged for

GDP in G

, and the released subunits initiate classical

pathways: inhibition of adenylate cyclase (decrease

in cAMP levels) as well as activation of phosphatidy-

linositol-3-kinase (PI3K) and the MAP-kinase cascade

(via Ras/ERK)  [8]. These signals lead to the different

effects in different cells: in neurons – to anti-apop-

totic cascades and growth; in endothelial cells – to

activation of endothelial nitric oxide synthase (eNOS)

and enhancement of the barrier function, and in

lymphocytes – to changes in the receptor expression

necessary for migration  [42]. S1P-R

is capable of in-

teracting with three types of G-proteins simultane-

ously: G

, G

, and G

. Its interaction with G

is particularly important: activation of S1P-R

leads

to activation of the small G-protein RhoA and its ef-

fector ROCK, which triggers cytoskeletal reorganiza-

tion – formation of stress fibers, contraction of the

cell’s actin-myosin cytoskeleton, and changes in the

cell shape. Simultaneously, via G

, S1P-R

can acti-

vate phospholipase C and increase cytoplasmic Ca

levels [43]. S1P-R

is similar to S1P-R

in that it is

also capable of binding to G

, G

, and G

. Activa-

tion of S1P-R

typically causes release of Ca

(via

the PLC/IP

pathway) and activation of the Rho sig-

naling and could also influence the MAPK signaling

pathway [44]. S1P-R

usually binds to G

and G

It is less well studied, but it is known that its acti-

vation influences migration of immune system cells

and certain processes of nervous system development

(presumably via Rho activation and interaction with

the transcription factor NF-κB) [45]. S1P-R

interacts

with G

and G

. Via G

it can activate the PI3K/Akt

signaling, and via G

– Rho/ROCK; overall S1P-R

in different cell types either inhibits migration (e.g.,

of oligodendrocytes – via Rho-activation) or promotes

survival (via Akt-activation)  [8].

S1P-receptors form a complex network of signal-

ing pathways. Their distribution across the organs

and cells largely determines outcome of the biolog-

ical effect of S1P. Each of the five receptors has a

characteristic pattern of expression in the tissues,

as shown in Table  2. Pharmacological modulation of

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

these receptors allows for selective influence on the

immune system and CNS, which forms the basis of

modern treatments for multiple sclerosis.

PHYSIOLOGICAL FUNCTIONS OF S1P

IN CNS AS A SIGNALLING MOLECULE

All S1P-receptors with exception of S1P-R

are

expressed in CNS by neurons and glial cells. S1P

signaling is essential for normal functioning of neu-

rogenesis and neuronal differentiation: activation of

the S1P-receptors stimulates proliferation of neuro-

nal precursors and enhances neuronal survival via

activation of the PI3K/Akt and MAPK/ERK signaling

pathways  [46]. Furthermore, S1P regulates synaptic

activity and neurotransmission such as activation of

the S1P-R

on neurons increases plasma membrane

excitability and neurotransmitter release, which con-

tributes to the effective synaptic transmission  [47].

S1P-R

, conversely, controls neuronal excitability, and

in the experimental studies deletion of the S1P-R

gene in mice led to neuronal hyperexcitability  [48].

S1P also plays a significant role in the process-

es of myelination and remyelination. Oligodendro-

cytes – the cells that form the myelin sheath – ex-

press several subtypes of S1P-receptors with S1P-R

being predominant in the mature oligodendrocytes.

The signaling pathway via S1P-R

promotes survival

of these cells by activating anti-apoptotic pathways

(e.g., PI3K/Akt), at the same time it could potentially

limit their migration via the Rho/ROCK pathway  [46].

S1P-R

, on the contrary, stimulates migration and

growth of oligodendrocytes involved in myelin forma-

tion. Simultaneous activation of S1P-R

and S1P-R

important for proper myelination: it has been shown

that the absence of S1P-R

in the experimental an-

imals leads to reduction in the myelin protein lev-

els and thinning of the myelin sheaths of axons  [49].

In the experimental models of demyelination (e.g.,

the cuprizone toxin model) stimulation of S1P-R

promotes remyelination; in particular, it was shown

that activation of this receptor type reduced oligoden-

drocyte apoptosis, prevented myelin loss, and accel-

erated its regeneration [50]. Furthermore, treatment

of the oligodendrocyte precursor cells with low doses

of S1P or fingolimod (an S1P analogue) in  vitro en-

hanced their differentiation into mature oligodendro-

cytes  [51]. These data suggest that the S1P signaling

could promote endogenous reparative processes in

the CNS (remyelination), which is particularly rele-

vant for the chronic stages of MS, when regenerative

potential of oligodendrocytes is virtually exhausted.

S1P also regulates a number of key functions in

astroglial cells. Astrocytes express S1P-R

and S1P-R

and upon exposure to certain growth factors they also

begin to express S1P-R

. The S1P signaling pathways

in astrocytes control their proliferation (via activation

of the ERK kinase cascade), migration, formation of

the intercellular contacts (e.g., gap junction commu-

nication), and secretion of growth factors  [52]. S1P is

also involved in the development of astrogliosis – re-

active proliferation of astrocytes during inflammation

or injury. It has been shown that under conditions of

pro-inflammatory stimulation, astrocytes upregulate

expression of the S1P-R

and S1P-R

receptors, and

activation of these receptors contributes to astroglio-

sis. In the astrocyte cultures, activation of S1P-R

selective agonists increased the level of expression

of pro-inflammatory molecules – cyclooxygenase-2,

interleukin-6, and vascular endothelial growth fac-

tor (VEGF) [53]. On the other hand, blocking the S1P

signaling in astrocytes could limit pathological pro-

cesses: for example, use of the functional S1P-R

an-

tagonist (the drug FTY720 – Fingolimod) suppressed

release of neurotoxic mediators from astrocytes  [54],

and thereby attenuated neurodegenerative chang-

es mediated by astrocytes and microglia. Inhibiting

S1P-R

in astrocytes in the experiments also reduced

neuropathic pain by enhancing secretion of the an-

ti-inflammatory cytokine interleukin-10  [55].

Microglia, which are resident innate immune

cells of the CNS, are also sensitive to S1P. Under phys-

iological conditions microglial cells predominantly ex-

press the S1P-R

and S1P-R

subtypes and remain in

a resting state. S1P functions as a chemotactic factor

for microglia: extracellular S1P is capable of induc-

ing directed migration of microglial cells towards the

site of injury. In the areas of acute brain tissue dam-

age, increase in the S1P concentration is observed,

which correlates with accumulation of microglia in

these regions  [56]. As microglial cells are activated,

there is a significant reorganization of the S1P-recep-

tor expression profile: surface expression of S1P-R

and S1P-R

decreases, while expression of S1P-R

in-

creases significantly. It is believed that activation of

S1P-R

contributes to the enhancement of pro-inflam-

matory responses in microglia through stimulation

of the Rho/ROCK signaling pathway and subsequent

reorganization of the actin cytoskeleton  [57]. Modula-

tion of the S1P signaling has a marked effect on the

functional state of microglia under conditions of neu-

roinflammation. In the model of experimental auto-

immune encephalomyelitis (EAE) the use of function-

al modulators/antagonists of S1P-R

and S1P-R

led to

the significant reduction in local neuroinflammation

caused by both microglial activation and infiltration

of the autoreactive T-cells. This was accompanied by

the improvement in the clinical course of the disease

in animals  [10]. The obtained data suggest that the

drugs that modulate the S1P- receptor signaling could

have a dual therapeutic effect: immunosuppressive

S1P – KEY SIGNALING MOLECULE IN NORMAL CONDITIONS AND IN MS 665

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

(through their effect on circulating lymphocytes) and

direct neuroprotective (by regulating functional ac-

tivity of the resident glial cells, primarily microglia).

Thus the “S1P-S1P-receptors” signaling system

represents a promising target for the development of

new treatment strategies for demyelinative diseases,

primarily multiple sclerosis, where combination of

the immunomodulatory and neuroprotective effects

could significantly improve prognosis and slow the

disease progression. Further research aimed at the

selective modulation of specific subtypes of S1P-re-

ceptors in various compartments of the CNS appears

necessary for the development of more effective and

safer therapeutic approaches.

METABOLIC EFFECTS OF S1P AND CERAMIDE

In addition to their roles as extracellular ligands

and intracellular signaling mediators, S1P and cera-

mide are involved in key metabolic processes in the

brain, influencing autophagy, mitochondrial function,

oxidative stress and apoptosis. Key enzymes in sphin-

golipid metabolism include sphingosine kinase-1 and

sphingosine kinase-2: “cytosolic” sphingosine kinase-1

(SphK1) is the most extensively studied enzyme in

the S1P metabolism. Basal SphK1 activity maintains

cellular balance of sphingosine and S1P; and upon

exposure of the cell to a range of agonists includ-

ing pro-inflammatory cytokines and various growth

factors, SphK-1 is activated via the ERK1/2-mediated

phosphorylation and its translocation to the plasma

membrane [58]. S1P produced by SphK1 exhibits an-

ti-apoptotic properties, promotes cell proliferation,

survival, and migration by stimulating AMPK, reduc-

ing oxidative stress, and modulating mitochondrial

function, as well as participating in neurogenesis

and synaptic plasticity  [59]. In MS, the increased ex-

pression of SphK1 in microglia and astrocytes exac-

erbates neuroinflammation via the NF-κB activation

and production of pro-inflammatory cytokines (IL-1β,

TNF-α) contributing to oligodendrocyte apoptosis and

demyelination. The SphK1-inhibitors demonstrate a

neuroprotective effect in the experimental models of

MS reducing inflammation, stimulating remyelination,

and slowing the disease progression  [60]. “Nuclear”

SphK2 is localized in the intracellular membrane

structures and is not secreted into the extracellular

space. SphK2 is found primarily in the cell nucleus;

and it inhibits the histone deacetylases HDAC1 and

HDAC2; thus, this enzyme mediates indirect influ-

ence of the sphingolipid metabolism on the regula-

tion of gene expression governing lipid and carbo-

hydrate metabolism as well as genes associated with

epigenetic regulation and response to DNA dam-

age  [58,  61].

In mitochondria, S1P modulates assembly and

function of the complex IV (cytochrome c oxidase) of

the respiratory chain and interacts with the protein

prohibitin-2, thereby ensuring efficient electron trans-

port and maintenance of cellular respiration thus

preventing an energy deficit  [62]. Systemically S1P

integrates with the pathways of steroidogenesis and

phospholipid metabolism influencing lipid metabo-

lism and maintaining energy balance in the tissues

with high metabolic activity including brain  [63].

In contrast, the “ceramide pathway” is often asso-

ciated with metabolic disorders. Accumulation of cera-

mides (e.g., C16:0) in the brain leads to mitochondrial

dysfunction, activation of the NLRP3 inflammasome,

and increased levels of IL-1β, which exacerbates neu-

roinflammation and neurodegeneration [64]. In the MS

pathogenesis, a metabolic shift towards predominance

of ceramides over S1P is observed: the elevated levels

of ceramides in plasma and brain tissues correlate

with the oligodendrocyte apoptosis, demyelination,

and disease progression. This disruption of the “sphin-

golipid rheostat” causes metabolic stress, including ac-

cumulation of the ceramide-enriched exosomes that

exert a toxic effect on the neighboring cells.

Thus, metabolic effects of S1P and ceramides

are closely intertwined with the signaling pathways

forming bidirectional links: metabolic shifts (e.g.,

activation of ceramidases or sphingosine-kinases,

which influence the levels of bioactive metabolites

of sphingolipid metabolism) affect signal transduc-

tion in the CNS, while signaling via the S1P-receptors

modulates metabolism. These interactions highlight

the role of the “sphingolipid rheostat” as an integra-

tor of metabolism and neuronal function in the CNS,

where imbalances lead to a cascade of pathological

events at the cellular and molecular levels (apopto-

sis, autophagy, mitochondrial dysfunction) through

to systemic manifestations (demyelination, neurode-

generation, remyelination). This not only deepens our

understanding of the MS pathogenesis, but also opens

up prospects for comprehensive therapy aimed at re-

storing metabolic balance.

S1P-DEPENDENT REGULATION

OF THE IMMUNE RESPONSE

Function, localization, and survival of the im-

mune system cells are largely determined by regula-

tion of the S1P signaling and S1P-receptors. Migration

and localization of the innate immune cells in the

sites of inflammation, exit of B- and T-lymphocytes

from the bone marrow and thymus, as well as their

recirculation through the secondary lymphoid organs

(including directed movement towards marginal zones

and subsequent entry into the systemic circulation)

GANIN, ZAKHAROVA666

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

depend to a large extent on the surface expression

of S1P-receptors (primarily S1P-R

) and formation of

the S1P concentration gradients between the differ-

ent tissue compartments. It has been experimentally

demonstrated that when the S1P levels in the blood

or lymph are reduced (e.g., pharmacologically) lym-

phocytes cease to leave the lymph nodes remaining

“trapped inside” – this leads to the rapid reversible

lymphopenic effect  [65]. Thus, maintenance of the

S1P-gradient and functional activity of S1P-R

on the

surface of lymphocytes is critical for normal immune

surveillance. Disruption of this gradient effectively

suppresses immune responses by preventing lympho-

cytes from leaving the organs of the lymphoid system.

S1P mediates migration of not only naive but also ac-

tivated lymphocytes. For example, upon initiation of

an immune response in a lymph node, the activated

T-lymphocytes, after some time, increase the level of

expression of S1P-R

which lets them to “leave” the

lymph node and “reach” the site of inflammation; this

process underlies organotropism of inflammation. In

autoimmune diseases, particularly MS, the autoaggres-

sive effector cells also utilize the S1P signaling path-

way for recirculation and penetration into the CNS.

In fact, exit of the autoreactive lymphocytes from

lymph nodes and their migration to the target tissues

constitute an S1P-dependent stage in the pathogen-

esis of autoimmunity. Pharmacological modulation

of this mechanism underlies the action of the entire

class of immunomodulators– functional S1P-R

-antag-

onists. Drugs of this group (Fingolimod, Siponimod,

Ozanimod and others) bind to S1P-R

on the surface of

lymphocytes causing internalization and degradation

of the receptor; due to this the cells temporarily lose

their ability to “sense” the S1P-gradient and “leave”

the lymphoid organs. This results in “retention” of a

significant proportion of T- and B-lymphocytes in the

lymph nodes, causing reduced lymphocytic infiltra-

tion of the target organs, and, consequently, reduction

in the immunopathological tissue damage.

In addition to lymphocytes, S1P influences func-

tion of many other immune cells. For example, mono-

cytes and neutrophils express various S1P-receptors

through which S1P can regulate their chemotaxis and

cytokine secretion. The S1P-gradient acts as a chemo-

tactic factor for monocytes at the sites of inflamma-

tion in a similar way to how it “attracts” microglia to

the sites of damage in the CNS  [66]. S1P can modulate

maturation of dendritic cells and migration of these

antigen-presenting cells to lymph nodes. Further-

more, S1P influences B-lymphocytes: their exit from

the spleen and lymph nodes is also regulated via

S1P-R

, and function of B-cells in the peripheral cir-

culation (e.g., antibody production) could depend on

the S1P levels in the microenvironment. The S1P-re-

ceptor modulators used in MS reduce the number of

both T- and B-lymphocytes circulating in the systemic

circulation, which leads to a weakening of both the

T-cell and humoral components of the autoimmune

process. In  MS, B-cells contribute to pathogenesis

through antigen presentation, secretion of pro-inflam-

matory cytokines (IFN-γ, TNF-α, IL-6), and synthesis of

antibodies against myelin; consequently their “reten-

tion” via the S1P-receptor modulators also contributes

to clinical improvement [67].

Inhibition of lymphocyte migration can be

achieved not only through the direct modulation

of S1P-receptors, but also by targeting enzymes in-

volved in the S1P metabolism, in particular by inhib-

iting sphingosine-1-phosphate lyase (SPL). Inhibition

of SPL leads to accumulation of S1P predominantly

in the lymphoid tissues (including lymph nodes and

the spleen), which enhances signaling via S1P-R

the surface of lymphocytes. Paradoxically, this causes

functional desensitization and internal degradation

of S1P-R

preventing lymphocytes from leaving lym-

phoid organs and inducing marked lymphopenia in

the peripheral blood.

Recent preclinical studies have demonstrated

that the selective inhibitors of SPL cause significant

increase in the S1P levels in lymphoid tissues accom-

panied by the marked lymphopenia and reduction

in clinical manifestations of EAE in the animals  [68].

This approach is considered an alternative immuno-

suppression strategy for autoimmune diseases, po-

tentially offering greater selectivity compared to the

S1P receptor modulators. It is hypothesized that the

SPL-inhibitors predominantly increase S1P concentra-

tions in the lymphoid compartments and only slightly

affect its levels in the CNS, which may reduce the

risk of side effects associated with the direct effects

on the resident CNS cells.

Furthermore, S1P plays a role in regulating the

innate immune system, in particular by influencing

the natural killer (NK) cells and invariant NKT (iNKT)

cells– a specialized population of T-lymphocytes that

recognize lipid antigens in the context of CD1d mol-

ecules  [69]. The iNKT cells are capable of producing

both pro-inflammatory (IFN-γ, IL-17) and anti-inflam-

matory (IL-4, IL-10, IL-13) cytokines, thereby modulat-

ing the balance of immune response in autoimmune

diseases  [70]. In MS, functional inactivity (anergy)

of the iNKT cells in response to endogenous sphin-

golipids is observed, which contributes to dysregula-

tion of the immune response  [71]. Experimental ap-

proaches have been suggested that aim to restore the

immunoregulatory function of iNKT cells by admin-

istering synthetic analogues of α-galactosylceramide

(α-GalCer) – a classic lipid antigen for CD1d. Such

analogues are capable of “reprogramming” iNKT-

cells towards predominant production of anti-in-

flammatory cytokines, which leads to suppression of

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

autoimmune damage to myelin in the EAE models  [72].

Although this mechanism is not directly associated

with the S1P signaling, it highlights central role of

the sphingolipid pathways in the fine-tuning of the

immune response and opens up the prospects for the

development of the new lipid-mediated immunomod-

ulatory strategies for autoimmune diseases includ-

ing MS. Further research is needed to assess safety,

selectivity, and clinical translational value of these

approaches.

S1P AND BLOOD-BRAIN BARRIER

Blood-brain barrier (BBB) is a multi-layered dy-

namic system formed by the endothelial cells of the

brain’s capillaries, which are closely connected by

tight junctions as well as by pericytes and astrocyte

processes. It acts as a filter controlling passage of

the cells and soluble molecules from the blood into

the CNS. In MS, an early event is disruption of the

integrity of BBB, which facilitates penetration of

immune cells to the CNS. S1P signaling is involved

in the regulation of BBB permeability and can both

protect the barrier and, in some cases, contribute to

its damage. Under normal physiological conditions,

S1P helps maintain tight junctions between the en-

dothelial cells, thereby strengthening the BBB. S1P-R

is highly expressed on the endothelial cells of the

CNS microvasculature. The S1P-S1P-R

signal in the

endothelium via activation of Akt/eNOS and a num-

ber of other pathways stimulate assembly of the tight

junction proteins – occludin and claudins – which re-

duces intercellular (paracellular) permeability of the

vascular wall  [73]. The S1P-S1P-R

signaling pathway

also counteracts lymphocyte migration through the

endothelial cells themselves (i.e. transcellular per-

meability of the vascular wall), thereby maintaining

the anti-inflammatory phenotype of the endothelium.

Experiments have shown that when this metabolic

signal is blocked, endothelial cells shift to the pro-in-

flammatory state, and connections between the cells

weaken – the endothelium becomes more “loose” and

permeable to the immune cells. Thus, the endogenous

S1P performs a protective function of the BBB.

However, under conditions of inflammation and

pathology, interactions between S1P and the BBB are

more complex. It has been observed that in neuroin-

flammation the action of S1P-receptors could have

a dual effect: on the one hand, activation of S1P-R

in the endothelium could increase the barrier’s im-

permeability reducing lymphocyte diapedesis (for

example, Fingolimod helps to stabilize intercellular

contacts in the endothelium, thereby reducing pen-

etration of the cells into the CNS) [74]. On the other

hand, some data suggest that under pathological

conditions the increased activation of other subtypes

of S1P-receptors could disrupt integrity of the BBB.

In particular, the S1P-R

expressed on the endothe-

lium is capable of inducing cytoskeletal remodeling

and formation of stress fibers upon excessive acti-

vation leading to the opening of intercellular gaps

and increased vascular permeability  [75]. In the EAE

model, it was shown that the S1P-R

expression in-

creases sharply in the cerebral vessels during the

acute phase, and the use of S1P-R

antagonists re-

duced the disease severity  [76]. Thus, balance of the

signals from different S1P-receptors could determine

the state of BBB during inflammation: predominance

of the S1P-R

signals strengthens the barrier, while

predominance of the S1P-R

signals weakens it. Astro-

cytes play a distinct role: they are a key component

of the neurovascular unit and together with the en-

dothelium form the BBB. The processes of astrocytes

surround the capillaries of the brain and release fac-

tors that influence permeability of the barrier. Astro-

cytes themselves are sensitive to S1P: their surface

bears S1P-R

and S1P-R

activation of which could

alter expression of the proteins important for the

endothelial-astrocytic contacts. It has been shown in

the cell culture experiments that upon inflammatory

activation of astrocytes S1P is capable of enhancing

expression of the matrix metalloproteinases, which

degrade the vascular basement membrane as well

as suppress production of angiopoietin-1 – a key fac-

tor supporting barrier function – by astrocytes  [53].

This could lead to disruption of the integrity of BBB.

On the other hand, Fingolimod, which also acts on

astrocytes, is capable of indirectly protecting the BBB:

it has been noted that its use reduces production of

the pro-inflammatory cytokines and chemokines by

astrocytes, attenuates reactive astrocytosis, and de-

creases recruitment of leukocytes to the vascular wall.

During the relapse of MS, an increase in per-

meability of the BBB has been observed, which

correlates with the appearance of areas of contrast

enhancement on the MRI scans. The studies with hu-

man endothelial cell cultures have confirmed that

Fingolimod strengthens intercellular contacts by in-

creasing cadherin levels in the endothelial adhe-

sion junctions [77]. Thus, targeting S1P-R

represents

a promising strategy for preserving BBB integrity

during neuroinflammation. Hence, S1P plays a “dual”

role in the regulation of BBB: under normal condi-

tions it is essential for maintaining barrier function,

but during inflammation an imbalance in activation

of the S1P-receptors could contribute to the impaired

barrier permeability. Therapeutic modulation of the

S1P signal (aimed at enhancing S1P-R

and blocking

S1P-R

) is considered as an approach to preserve

integrity of BBB and prevent penetration of autore-

active immune cells into the CNS.

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

ROLE OF S1P IN PATHOGENESIS

OF MULTIPLE SCLEROSIS

Multiple sclerosis is a disease with complex

pathogenesis involving activation of autoimmune re-

actions against myelin components and subsequent

progressive axonal damage. It is believed that the

onset of the disease is associated with appearance of

T-lymphocytes in the peripheral immune system that

recognize myelin antigens. In the healthy individuals

the autoaggressive lymphocytes are usually eliminat-

ed or kept in an inactive state (central and peripheral

tolerance). However, in the presence of genetic pre-

disposition and under the influence of external fac-

tors (infections, vitamin D, smoking, etc.), a pool of

autoaggressive T-cells targeting myelin proteins could

form. Such antigens include the main components of

the myelin sheath: MBP, PLP, and others.

Indeed, in the patients with MS, the CD4

and

CD8

T-lymphocytes specific to MBP and PLP epi-

topes and producing pro-inflammatory cytokines

(IL-2, IFN-γ, TNF-α) are detected in peripheral blood

[78]. It is believed that activation of such autoaggres-

sive lymphocytes in the periphery is the first stage

of the pathological cascade. The activated CD4

Th1

and Th17 cells as well as cytotoxic CD8

T-cells and

autoreactive B-cells undergo clonal expansion and

begin to express adhesion molecules and chemokine

receptors, enabling them to migrate into the CNS  [79].

As noted earlier, S1P via S1P-R

facilitates exit of the

autoreactive lymphocytes from the lymphoid organs

into the peripheral bloodstream. Without the S1P sig-

nal, the autoaggressive T- and B-cells would remain

“trapped” in the lymph nodes and spleen and would

be unable to penetrate the CNS. Consequently S1P-R

acts as a catalyst for the autoimmune process – an

elevated or normally functioning S1P signal facilitates

onset of an autoimmune attack. This is confirmed by

the fact that the S1P-R

blockade significantly attenu-

ates the course of EAE in animals preventing penetra-

tion of the aggressive lymphocytes into the CNS [80].

The next stage in the pathogenesis involves lympho-

cytes crossing the BBB and penetrating the CNS. The

T-cells expressing integrins [e.g., very late antigen-4

(α4β1 integrin) – VLA-4] attach to the adhesion mol-

ecules on the endothelium of the cerebral blood ves-

sels (vascular cell adhesion molecule  1, VCAM-1) and

pass through the BBB via diapedesis  [81]. Once in the

CNS parenchyma, they are reactivated by the local

antigen-presenting cells (APCs) (dendritic cells, mi-

croglia), which present myelin components to them

in complex with the major histocompatibility com-

plex (MHC) class  II. The reactivated T-lymphocytes

begin to secrete inflammatory cytokines, primari-

ly IFN-γ, TNF-α, IL-17, and granulocyte-macrophage

colony-stimulating factor (GM-CSF), which leads to

exacerbation of local inflammation, recruitment

of new immune effector cells, and damage to oli-

godendrocytes  [79]. IFN-γ and TNF-α increase per-

meability of the BBB exacerbating its damage and

are directly toxic to oligodendrocytes and neurons.

IL-17 promotes endothelial activation, while GM-CSF

is essential for the recruitment and activation of

monocytes  [82].

As discussed earlier, S1P can both maintain in-

tegrity of the BBB and contribute to its increased

permeability during inflammation. It is likely that in

the acute phase of MS against the background of el-

evated concentrations of pro-inflammatory cytokines,

the protective role of S1P-R

diminishes and BBB be-

comes permeable precisely in the presence of S1P.

However, as the active inflammation subsides, the

S1P-R

signaling could contribute to the restoration of

the barrier. Furthermore, according to the available

data, the S1P-R

expressed on endothelial cells and

astrocytes could be involved in pathological barrier

permeability in MS. Although there is a little direct

clinical evidence to support this, S1P-R

is considered

a potential target: its blockade is a possible way to

reduce neuroinflammation complementing the effect

of selective stimulation of S1P-R

Microglia and macrophages are activated within

the demyelinating lesion under the influence of cy-

tokines; at the same time, they phagocytose myelin

debris and themselves exacerbate the damage by re-

leasing reactive oxygen species, proteases, and pro-in-

flammatory cytokines. A  vicious cycle is formed:

immune cells destroy myelin, the released antigen

intensifies the immune response, and the resulting

inflammation causes increase of the damage to the

nervous tissue. Concurrently, B-lymphocytes that en-

ter the CNS differentiate into the plasma cells and

produce antibodies against myelin antigens, which

form immune complexes and activate the comple-

ment system, thereby accelerating destruction of my-

elin and axons. B-cells could also function as local

APCs sustaining activity of the pathogenic T-cells.

Consequently, demyelinating lesions characteristic of

MS are formed – areas in the white and subsequently

grey matter of the brain where the myelin sheath is

destroyed, axonal conduction is impaired, and there

are infiltrates of immune cells and reactive glial cells.

In the demyelinating lesions, S1P actively influences

microglial cells and astrocytes. As mentioned earlier,

S1P acts as a chemoattractant for microglia: the el-

evated levels of S1P have been detected in the de-

myelinating lesions. This may be due to the release

of S1P from the damaged cells or from the activated

endothelial cells. Microglia migrating in response to

this signal, on the one hand, participate in phagocy-

tosis of the myelin degradation products, which is

beneficial for the subsequent remyelination; on the

S1P – KEY SIGNALING MOLECULE IN NORMAL CONDITIONS AND IN MS 669

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

other hand, they themselves exacerbate inflammation

and release neurotoxic substances worsening axonal

damage. Interestingly, inhibition of the S1P-R

in as-

trocytes and microglia reduces production of certain

chemotactic factors. In particular, it was shown in the

experiment that blocking of the S1P-R

signal sup-

pressed the release of the chemokine CXCL5 by astro-

cytes and microglia, thereby potentially reducing in-

flux of the new immune cells into the lesion site  [83].

This demonstrates that the S1P signaling in the glial

cells sustains local inflammation in MS. Furthermore,

the S1P-R

activation increases synthesis of pro-in-

flammatory factors [IL-6, Cyclooxygenase-2 (COX-2),

etc.] by astrocytes  [53], i.e. reactive astrocytes ampli-

fy the inflammatory response under the influence of

S1P. Thus, within the demyelinating lesion, S1P pro-

motes pathological interaction between the immune

cells and neuroglia sustaining persistence of inflam-

mation. Over time, chronic inflammation progresses

to the phase of neurodegeneration: damaged axons,

lost neurons, and glial tissue are found within and

around the demyelinating lesions. It is believed that

each new relapse of MS causes irreversible damages

to axons, which accumulate and lead to progressive

neurological deficits. In the later stages of MS neu-

rodegeneration could be sustained without the direct

involvement of immune cells due to the chronic ac-

tivation of microglia, cytokine imbalance, and degen-

erative changes in the CNS environment (e.g. accu-

mulation of the neurotoxic metabolic by-products). In

this context, the mechanisms of endogenous remye-

lination are of particular interest. The S1P-R-mediated

signaling could stimulate differentiation of the oligo-

dendrocyte precursor cells. In the acute demyelinat-

ing lesions in MS, partial remyelination (the so-called

“shadow” demyelination with thin myelin sheaths) is

frequently observed, which is associated with the ac-

tivity of surviving oligodendrocytes. It is hypothesized

that the S1P present in the tissues could contribute

to this spontaneous remyelination, for example by

stimulating migration of the oligodendrocyte precur-

sor cells to the affected axons and accelerating their

maturation. However, in the progressive forms of MS,

depletion of the remyelination potential is observed,

largely due to depletion of the pool of oligodendro-

cyte precursor cells and unfavorable microenviron-

ment. Sphingolipid imbalances in MS (elevated cer-

amide levels, reduced S1P) may contribute to this

problem. Consequently, the S1P-receptors are regard-

ed as important regulators of remyelination process-

es in the CNS. Cells of the oligodendrocyte lineage

express several subtypes of these receptors (S1P-R

S1P-R

, S1P-R

, and S1P-R

) with their expression lev-

els changing as the cells mature. The oligodendrocyte

precursors are characterized by the predominance of

the S1P-R

expression, whereas S1P-R

dominates in

the mature oligodendrocytes. This differentiation-de-

pendent distribution of the receptors determines their

functional specialization in regulating the key stages

of remyelination: S1P-R

primarily regulates prolifera-

tion of the oligodendrocyte precursor cells by activat-

ing intracellular signaling cascades including ERK1/2,

Akt, and p38MAPK and migration via activation of

the signaling pathways associated with the Rho-de-

pendent regulation of cell motility, at the same time,

S1P-R

regulates differentiation and survival of the

mature oligodendrocytes  [84]. Taken together these

findings suggest that the S1P-R-mediated signaling is

involved in regulating proliferation, migration, and

differentiation of the oligodendrocyte lineage cells

as well as in maintaining survival of the mature oli-

godendrocytes. Thus, modulation of the “S1P-S1P-R”

pathway could be considered a potential therapeutic

approach aimed at enhancing remyelination process-

es in MS.

In MS, disruption of the “sphingolipid rheostat”

has been observed: reduced levels of S1P against the

background of ceramide accumulation in the affect-

ed tissues. This shift towards a “pro-apoptotic” state

could impair the function of oligodendrocytes and my-

elin regeneration. Thus, in the inactive demyelinating

lesions accumulation of the long-chain ceramides  [85]

and reduction in the certain neuroprotective gan-

gliosides were observed, which correlated with the

disease activity [86]. Elevated concentrations of cer-

amides (C16:0, C24:1, etc.) and sphingosine together

with the reduction in sphingomyelin are also found

in the blood plasma of the patients in the acute phase

of MS  [85]. These changes indicate predominance of

the sphingomyelin degradation pathways and accu-

mulation of the pro-apoptotic metabolites. It was ex-

perimentally demonstrated in the study that activity

of the acid sphingomyelinase in the blood plasma

of the patients with multiple sclerosis increased by

58%, as well as activity of alkaline ceramidase also

increased in the erythrocytes, which together con-

tributes to the enhanced formation of ceramide and

sphingosine and is accompanied by the relatively low

level of S1P  [87]. Such shift in metabolism is quite

capable of exacerbating the death of oligodendro-

cytes and neurons within the lesions. Furthermore,

an interesting theory regarding the MS progression

involves exosomes: during chronic inflammation mi-

croglia release exosomes enriched with ceramides and

other lipids, which diffuse into the brain tissue and

induce secondary damage to oligodendrocytes beyond

the primary demyelinating lesion. The elevated cera-

mide levels in exosomes correlated with the greater

degree of demyelination; it is believed that these ex-

tracellular vesicles trigger oligodendrocyte apoptosis

in the new areas contributing to the expansion of the

lesion [88, 89]. Thus, the altered sphingolipid profile

GANIN, ZAKHAROVA670

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

not only accompanies, but may also stimulate the MS

progression.

CONCLUSIONS

Sphingosine-1-phosphate (S1P) is not merely a

bioactive metabolite of the sphingolipid metabolism,

but an integrative signaling molecule that links met-

abolic processes to the functions of the cells in the

CNS and immune system both under normal con-

ditions and in pathological states. Acting via the

S1P-R

-S1P-R

and intracellular targets, S1P regulates

cell viability, autophagy, mitochondrial function, re-

dox balance, and gene expression, thereby controlling

metabolic pathways associated with the resistance of

neural tissue to damage and its reparative potential.

At the same time, S1P is involved in regulation of the

lymphocyte migration, BBB permeability, reactivity of

astrocytes and microglia, as well as survival, differ-

entiation, and functional activity of oligodendrocytes.

Thus, S1P mediates the link between the lipid metab-

olism and specific signaling functions of the brain.

These functions include maintenance of neuronal

excitability and synaptic transmission, intercellular

communication within the neurovascular unit, and

the process of remyelination. In other words, S1P is

involved not only in the metabolic support of the CNS

cells, but also in the regulation of the mechanisms

that determine nerve impulse conduction, stability of

neuroglial interactions, and structural and functional

integrity of the brain tissue.

In MS, disruption of the “sphingolipid rheostat”

characterized by the shift of the balance towards ac-

cumulation of ceramides and relative decrease in the

S1P levels may be regarded as one of the mechanisms

by which the system switches from the adaptive-re-

parative state to the pro-inflammatory and pro-apop-

totic one. This shift is associated with mitochondrial

dysfunction, increased oxidative stress, activation of

microglia and astrocytes, increased permeability of

BBB, impaired oligodendrocyte survival, and reduced

remyelination potential. Consequently, not only cellu-

lar metabolic homeostasis is disrupted, but also key

processes ensuring structural and functional integrity

of the CNS including neuroglial interactions, barrier

function of the BBB, and remyelination. Thus, the

“S1P–S1P receptor” axis should be regarded as one

of the central mechanisms of bidirectional commu-

nication between metabolism and specific functional

organization of the brain in MS. This may explain

high therapeutic significance of the S1P-dependent

signaling: its modulation allows simultaneous influ-

ence on the immune cell migration, BBB permea-

bility, glial cell reactivity, and reparative processes

in the CNS. Pharmacological modulation of the S1P

signaling has already demonstrated clinical efficacy:

functional antagonists/modulators of S1P-receptors

(Fingolimod, Siponimod, Osanimod, Ponesimod etc.)

reduce activity of the autoimmune process primar-

ily by disrupting the S1P-dependent regulation of

lymphocyte migration and also potentially exert di-

rect effects in the CNS through their influence on

the glial cells and endothelium. However, significant

limitations remain related to the tissue and recep-

tor non-specificity, inter-individual variability in re-

sponse, as well as incomplete understanding of the

components of the S1P system determining transition

from the inflammatory phase to the neurodegenera-

tive phase. Deeper understanding of the variability in

the biological effects of S1P signaling under different

conditions would provide the basis for the develop-

ment of more selective and safer therapeutic strate-

gies for MS aimed not only at suppressing neuroin-

flammation but also at supporting remyelination and

slowing neurodegenerative component of the disease.

Abbreviations

APCs antigen-presenting cells

BBB blood-brain barrier

CNS central nervous system

EAE experimental autoimmune encephalo-

myelitis

eNOS endothelial nitric oxide synthase

GM-CSF granulocyte-macrophage colony-stimu-

lating factor

GPCR G-protein-coupled receptor

HDL high-density lipoprotein

MBP myelin basic protein

MS multiple sclerosis

PLP proteolipid protein

S1P sphingosine-1-phosphate

S1P-R

1-5

sphingosine-1-phosphate receptors

(subtypes 1-5)

SPL sphingosine-1-phosphate lyase

VLA-4 very late antigen-4 (α4β1 integrin)

Contributions

D.A.  Ganin: search and analysis of the literature, man-

uscript writing. M.N.  Zakharova: study concept and

design, manuscript editing, supervision.

Funding

The study was conducted without external funding.

Ethics approval and consent to participate

This work does not contain any studies involving hu-

man and animal subjects.

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

S1P – KEY SIGNALING MOLECULE IN NORMAL CONDITIONS AND IN MS 671

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

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