KLHL3 functions as a substrate-specific adapter protein in a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates ion transport in the kidney's distal nephron 1. The primary mechanism involves KLHL3-CUL3 complex-mediated ubiquitination and proteasomal degradation of WNK kinases (WNK1, WNK4, and WNK3), which are activators of the Na-Cl cotransporter NCC in distal convoluted tubule cells 12. This degradation pathway controls NaCl reabsorption and potassium secretion in the kidney. KLHL3 contains kelch repeats at its C-terminus and recognizes WNK4 through both an acidic motif and a novel C-terminal motif 3. The protein undergoes O-GlcNAcylation, which may regulate its function 4. Mutations in KLHL3 cause Familial Hyperkalemic Hypertension (Gordon syndrome), characterized by hypertension, hyperkalemia, and metabolic acidosis 125. Disease-causing mutations typically affect the Kelch domain, impairing KLHL3's ability to bind and degrade WNK kinases, leading to their accumulation and subsequent overactivation of NCC 2. KLHL3 is also implicated in other conditions including primary hyperparathyroidism, diabetes mellitus, and cardiovascular diseases 5.