WNK3 is a serine/threonine kinase on chromosome X.22 that plays a central role in electrolyte homeostasis and cell volume regulation 1. As a component of the WNK3-SPAK/OSR1 kinase cascade, WNK3 senses hyperosmotic stress and cell shrinkage through a volume-sensitive mechanism independent of chloride concentration 2. Upon activation, WNK3 undergoes liquid-liquid phase separation to form membraneless compartments that concentrate substrates OXSR1/OSR1 and STK39/SPAK, promoting their phosphorylation and downstream regulation of cation-chloride cotransporters 3. WNK3 directly phosphorylates and activates Na-K-Cl cotransporters (NKCC1, NKCC2) while inhibiting K-Cl cotransporters (KCC1-3), collectively promoting ion influx and preventing efflux 4. Additionally, WNK3 regulates intracellular potassium levels independent of chloride sensing 5 and enhances TRPV5/TRPV6-mediated calcium influx. Pathogenic WNK3 variants cause X-linked intellectual disability with variable epilepsy through impaired KCC2 phosphoregulation, critical for synaptic inhibition development 6. WNK3 dysfunction is also associated with Prieto syndrome and contributes to vascular and renal pathology in diabetes 7.