RNLS (renalase) is a bifunctional FAD-dependent amine oxidase with distinct intracellular and extracellular roles 1. Intracellularly, RNLS catalyzes oxidation of dihydro-NAD(P) forms to NAD(P)+ and regulates mitochondrial function and cell metabolism 12. When secreted by the kidney, RNLS functions as a signaling molecule independent of enzymatic activity, circulating systemically to modulate cardiac function and blood pressure by decreasing contractility, heart rate, and catecholamine levels [UniProt]. RNLS has emerged as a pleiotropic survival factor with protective effects across multiple organ systems. Kidney-targeted RNLS agonists prevent cisplatin-induced chr10 kidney disease by inhibiting regulated necrosis and preserving renal epithelial structures 3. RNLS exhibits prosurvival and anti-inflammatory effects in acute pancreatitis and gastrointestinal injury 4. Conversely, RNLS inhibition protects pancreatic β cells from diabetogenic stress by promoting glycolytic metabolism 2 and enhances anti-tumor immunity by promoting T cell activation, particularly when combined with anti-PD-1 therapy in melanoma 5. Genetic variants in RNLS (rs10887800 and rs2576178) increase preeclampsia susceptibility 6, suggesting pathogenic roles in hypertensive disorders. These diverse functions position RNLS as a therapeutic target with context-dependent applications—protective augmentation for organ injury and inhibition for cancer and diabetes.