S1P

Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator derived from sphingolipids. It influences a range of physiological processes by signaling through cell-surface receptors and, to a lesser extent, by intracellular targets.

S1P is produced primarily by phosphorylation of sphingosine via sphingosine kinases, SphK1 and SphK2. It is degraded by S1P phosphatases and by S1P lyase, which irreversibly cleaves S1P. In the bloodstream, S1P is carried by albumin and by apoM-containing high-density lipoprotein (HDL). It is also actively transported out of cells by specific transporters, creating gradients that regulate signaling in different tissues.

S1P signals mainly through five G protein-coupled receptors, S1PR1–S1PR5, which have distinct tissue distributions and couplingpreferences. S1PR1 is particularly important for lymphocyte egress from lymph nodes and vascular barrier integrity; S1PR2 and S1PR3 participate in vascular and smooth muscle signaling; S1PR4 and S1PR5 are enriched in immune and neural tissues, respectively. Receptor signaling can influence cell migration, survival, angiogenesis, and inflammatory responses, with outcomes depending on receptor subtype and context.

Physiological roles of S1P include regulation of the immune system, vascular development and endothelial barrier function, angiogenesis, and neural development and maintenance. The S1P gradient between blood and tissues guides immune cell trafficking, notably T cell egress from lymph nodes.

Clinically, modulators of S1P signaling, such as fingolimod (FTY720), are used to treat multiple sclerosis by sequestering lymphocytes in lymph nodes. S1P signaling is also investigated in cancer, fibrosis, and neurodegenerative diseases, with ongoing research into therapeutic targeting and biomarker applications.