Sphingosine-1-phosphate: Mechanisms and therapeutic potential in wound repair

Chronic wounds remain a significant clinical challenge due to impaired angiogenesis, persistent inflammation, defective tissue remodeling, and the limited effectiveness of current therapies. Consequently, the development of regenerative approaches capable of modulating multiple stages of wound repair has gained considerable attention. Among emerging therapeutic candidates, sphingosine-1-phosphate (S1P), a bioactive lipid, has shown substantial potential in promoting tissue regeneration. This review summarizes the biological functions of S1P during the hemostasis, inflammation, proliferation, and remodeling phases of wound repair. Particular emphasis is placed on receptor-mediated signaling through S1P receptors (S1PR1-S1PR5) and their downstream pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), and Rho GTPase signaling. These pathways regulate key cellular processes such as immune modulation, angiogenesis, fibroblast activation, keratinocyte migration, and extracellular matrix remodeling. S1P also promotes myofibroblast differentiation and vascular maturation while balancing pro- and anti-inflammatory responses, thereby reducing chronic inflammation and excessive fibrosis. Recent advances in biomaterial-based delivery systems have enhanced the therapeutic application of S1P. Hydrogels, nanofibers, decellularized scaffolds, liposomal formulations, and extracellular vesicle-based platforms enable localized and controlled S1P release, leading to improved healing outcomes in diabetic and chronic wounds. Furthermore, biomaterial properties, including surface chemistry, porosity, and mechanical characteristics, significantly influence cell-material interactions and S1P-mediated responses. Despite promising findings, the efficacy of S1P-based therapies depends on receptor selectivity, dosage, release kinetics, and the local wound microenvironment. Future studies should focus on designing bioresponsive, receptor-targeted delivery systems to achieve precise spatiotemporal control of S1P signaling and maximize regenerative outcomes with minimal adverse effects.