SPHK2 (sphingosine kinase 2) catalyzes the phosphorylation of sphingosine to generate sphingosine-1-phosphate (S1P), a bioactive lipid mediator with pleiotropic cellular functions 1. Unlike the pro-survival SPHK1 isoform, SPHK2 generally promotes apoptosis and enhances intracellular ceramide levels, thereby inhibiting cell growth 2. SPHK2 functions in multiple cellular compartments with distinct roles: in the nucleus, it inhibits histone deacetylases (HDAC1/2) through S1P production, upregulating histone acetylation (H3-K9, H4-K5, H2B-K12) to epigenetically regulate gene expression 3; in mitochondria, S1P binds PHB2 to modulate cytochrome c oxidase assembly and respiratory function. SPHK2 has emerged as a pivotal regulator in multiple pathological contexts. In pulmonary hypertension, elevated SPHK2 (up to 20-fold) drives vascular remodeling through histone H3K9 hyperacetylation in smooth muscle cells 3. In ischemic stroke, SPHK2 provides neuroprotection by mitigating blood-brain barrier disruption and neuroinflammation 4. SPHK2 also regulates hepatic lipid metabolism by controlling VLDL secretion through mTORC2-dependent regulation of SNARE complex stability 5. Additionally, SPHK2 modulates macrophage-mediated liver fibrogenesis via the AhR/NF-κB and AhR/S1P axes 6. In cardiovascular physiology, S1P signaling (produced by both SPHK isoforms) orchestrates endothelial function, vascular tone, and cardiac responses 7, with dysregulation linked to hypertension, atherosclerosis, and heart failure.