SphK

SPHK refers to sphingosine kinase, a family of lipid kinases that catalyze the phosphorylation of sphingosine to sphingosine-1-phosphate (S1P). In humans, the two major isoforms are SphK1 and SphK2, encoded by the SPHK1 and SPHK2 genes. The enzymes share a conserved kinase domain but differ in regulatory features and cellular distribution. SphK1 is primarily cytosolic and translocates to the plasma membrane upon activation, whereas SphK2 localizes to the nucleus, mitochondria, and endoplasmic reticulum.

The catalytic reaction uses ATP to add a phosphate to the 1-hydroxyl group of sphingosine, generating S1P. S1P functions as a potent signaling lipid that can act extracellularly by binding to a family of G protein–coupled receptors known as S1PR1–5, regulating cell survival, proliferation, migration, angiogenesis, and immune cell trafficking. S1P can also exert intracellular effects in certain contexts, including potential regulation of gene expression and organelle function. The balance between ceramide, sphingosine, and S1P—often described as the sphingolipid rheostat—helps determine cell fate decisions.

Physiologically, the SPHK/S1P axis participates in vascular integrity, neural development, and immune responses. Pathologically, dysregulation is linked to cancer, inflammatory diseases, fibrosis, and neurodegenerative conditions. In cancer, SphK1 activity is frequently associated with enhanced survival and resistance to therapy, while SphK2 can have context-dependent roles.

Therapeutically, SPHKs are targeted by small-molecule inhibitors and modulators. Examples include PF-543, a selective SphK1 inhibitor; opaganib (ABC294640), a SphK2 inhibitor studied in cancer and inflammatory diseases; safingol, a nonselective SPHK inhibitor; and SKI-II, a dual SphK1/2 inhibitor. These agents are primarily used in research and clinical investigations to probe sphingolipid signaling and its disease relevance.