Sphingosine-1-phosphate signaling in respiratory diseases: mechanisms and therapeutic perspectives.

Sphingosine-1-phosphate (S1P) is a pivotal bioactive sphingolipid functioning as both a structural membrane component and a signaling mediator. It orchestrates diverse physiological and pathological processes including cellular proliferation, migration, differentiation, and immune regulation. The biological efficacy of S1P is controlled by metabolic networks that coordinate its biosynthesis, transport, and degradation to maintain intra/extracellular homeostasis and to activate cell surface S1P receptors (S1PRs) to initiate downstream signaling. Contemporary research increasingly has increasingly revealed the multifaceted roles of S1P signaling in respiratory pathologies, including asthma, chronic obstructive pulmonary disease (COPD), pulmonary malignancies, and especially infectious lung diseases such as COVID-19 and influenza. Particularly, S1P levels are significantly correlated with the severity and prognosis of the disease. These findings indicate that pharmacological modulation of the S1P signaling axis, through sphingosine kinase (SPHK1/2) inhibition, S1P lyase (SPL) inhibition, or the S1PR modulation represents a promising therapeutic approach. However, incomplete understanding of the S1P signaling mechanisms presents significant challenges for clinical applications. This review systematically consolidates recent advances in S1P signaling research in respiratory medicine, with particular emphasis on delineating cellular and molecular mechanisms and evaluating the translational potential of targeted therapeutics.