OSR1 (oxidative stress-responsive kinase 1) is a serine/threonine protein kinase that functions as a critical regulator of ion homeostasis through phosphorylation of cation-chloride cotransporters 1. As a component of the WNK-SPAK/OSR1 kinase cascade, OSR1 is activated by WNK kinases via phosphorylation and subsequently phosphorylates sodium-potassium-2-chloride (NKCC) and sodium-chloride (NCC) cotransporters to regulate cellular ion transport 2. The kinase possesses a conserved C-terminal domain (CCT) that binds RFx[V/I] peptide motifs from upstream WNK kinases, enabling activation 3. OSR1 activation can be triggered through Piezo1-mediated calcium signaling in response to osmotic stress 4. During embryonic development, OSR1 marks ureteric bud progenitors and plays roles in kidney organogenesis 5. Physiologically, WNK-SPAK/OSR1 pathway inhibition decreases renal NaCl reabsorption and maintains serum potassium while lowering blood pressure 1. Pathologically, the pathway contributes to stroke pathology through NKCC1 over-activation, making WNK-SPAK/OSR1 inhibition a potential therapeutic strategy for hypertension, stroke, and neurological disorders including epilepsy and neuropathic pain 61.