SPHK1 (sphingosine kinase 1) is a key enzyme that phosphorylates sphingosine to generate sphingosine-1-phosphate (S1P), a critical signaling lipid mediator. Beyond its canonical kinase function, SPHK1 possesses serine acetyltransferase activity on COX2/PTGS2, which promotes neuroinflammatory resolution through specialized pro-resolving mediator production 1. SPHK1 drives multiple pro-tumoral processes including cell proliferation, angiogenesis, migration, and invasion across various cancer types 1. In the tumor microenvironment, SPHK1 facilitates immune evasion by promoting PD-L1 expression via the MAPK1-MMP1 axis in head and neck squamous cell carcinoma 2, and by activating NLRP3 inflammasome in tumor-associated macrophages, leading to CD8+ T cell exhaustion in colorectal cancer liver metastasis 3. SPHK1 promotes macrophage recruitment and M1/M2 polarization in liver fibrosis through C-C motif chemokine ligand 2 and the ASK1-JNK/p38 signaling pathway 4. In intracerebral hemorrhage, the Sphk1/S1P pathway promotes blood-brain barrier breakdown via NLRP3-mediated endothelial pyroptosis 5. SPHK1 elevation correlates with poor prognosis in colorectal cancer through epithelial-to-mesenchymal transition promotion 6. S1P signaling through S1PR1 also modulates T cell alloreactivity during transplantation 7. These findings identify SPHK1 and S1P as therapeutic targets for cancer immunotherapy, fibrosis, and neuroinflammatory diseases.