{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSphingosine kinase 1 (SPHK1) is a pivotal enzyme that phosphorylates sphingosine to yield sphingosine‐1‐phosphate (S1P), a bioactive lipid second messenger that regulates a wide array of cellular processes. Its activation is mediated by agonist‐induced phosphorylation events (for example, phosphorylation at Ser225 by ERK1/2), protein kinase C activation, and critical lipid–protein interactions that promote its translocation from the cytosol to the plasma membrane. Furthermore, SPHK1 function is modulated by interactions with signaling molecules such as TRAF2 and CIB1, while conserved residues in its structure ensure selective binding to phospholipids that target the enzyme to appropriate membrane sites."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn pathophysiological settings, SPHK1 emerges as a critical survival and oncogenic factor. Elevated SPHK1 activity promotes anti‐apoptotic signaling via the PI3K/Akt and NF‑κB pathways, contributing to cell proliferation, chemoresistance, and the enhanced production of inflammatory mediators. Such oncogenic roles have been documented in several cancers – including those of the breast, colon, prostate, and stomach – where high SPHK1 expression correlates with tumor progression, metastasis, and poor clinical prognosis. In addition, SPHK1‐derived S1P participates in restoring endothelial barrier function during inflammatory stress and modulates mast cell degranulation and cytokine release, further underscoring its significance in inflammation and immunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSPHK1 expression and activity are also intricately controlled by regulatory noncoding RNAs and other post‐transcriptional mechanisms. For instance, long noncoding RNAs such as HULC and Khps1 have been shown to up‐regulate SPHK1 via E2F1‐dependent promoter activation, whereas microRNAs like miR‑124 suppress its expression and attenuate tumorigenicity. Moreover, specialized isoforms of SPHK1 are secreted by endothelial cells to establish the vascular S1P gradient, and SPHK1 activity contributes to cellular adaptation under hypoxic conditions by modulating HIF‑1α stabilization. Additionally, inhibition of SPHK1 – whether by DNA damaging agents that trigger its proteasomal degradation or by small‑molecule inhibitors that promote autoinhibition – can shift the sphingolipid rheostat to favor apoptosis and restore insulin sensitivity. Crosstalk between SPHK1 and receptor tyrosine kinases, including EGFR, further emphasizes its multifaceted roles in both normal physiology and disease, making it a promising target for therapeutic intervention."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Pu Xia, Lijun Wang, Paul A B Moretti, et al. 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