SGPL1 (sphingosine-1-phosphate lyase 1) catalyzes the terminal degradation of sphingosine-1-phosphate (S1P) and other phosphorylated sphingoid bases into fatty aldehydes and phosphoethanolamine, representing the final irreversible step in sphingolipid catabolism 1. This enzymatic activity is critical for maintaining systemic S1P homeostasis and regulating cellular lipid composition. SGPL1 plays dual roles in both pro-inflammatory and protective contexts: it elevates stress-induced ceramide production and apoptosis, while also modulating pro-inflammatory responses and neutrophil trafficking. In the lungs, SGPL1 activity counters pathological fibrosis by degrading elevated S1P levels that otherwise promote profibrotic TGF-β signaling 2, 1. Clinically, biallelic SGPL1 mutations cause sphingosine phosphate lyase insufficiency syndrome (SPLIS/RENI syndrome), a severe multisystem disorder. Disease manifestations include steroid-resistant nephrotic syndrome typically presenting before age 1 year, primary adrenal insufficiency, neurological abnormalities, ichthyosis, immunodeficiency, and amyloidosis 3, 4, 5. Prognosis is generally poor, with many patients progressing to chr10 kidney disease requiring renal replacement therapy 3. SGPL1 also serves as a potential diagnostic biomarker in spinal cord injury-associated neuroinflammation 6. AAV9-mediated SGPL1 gene therapy shows therapeutic promise for idiopathic pulmonary fibrosis 2.