SphK1/S1P signaling network: From molecular mechanism to therapeutic targeting

Sphingosine kinase 1 (SphK1) is a key rate-limiting enzyme in the sphingolipid metabolic network. It generates sphingosine-1-phosphate (S1P) by catalyzing the phosphorylation of Sphingosine (Sph). It plays a key regulatory role in various physiological and pathological processes such as cell proliferation, survival, migration, inflammatory response and immune regulation. SphK1 closely connects intracellular lipid metabolism with extracellular GPCR signaling network, forming a complex "inside-out" signal transduction system. In this review, we focus on the current understanding of SphK1, including its structure characteristics, activation mechanism and signal transduction pathway. We also review the roles of SphK1 pathway in tumor, inflammation and immunity, cardiovascular, nervous system, digestive system, respiratory system and metabolic disease. Establishing a correlation between SphK1 or the SphK1/S1P signal axis and targeted drugs such as inhibitors, agonists, even some natural Chinese medicines, provides important theoretical support for understanding the potential of SphK1 as a therapeutic target. Finally, we propose future research directions based on current advances and shortcomings.