SLC9B2 encodes NHA2, an electroneutral Na+/Li+/H+ antiporter that extrudes sodium or lithium ions in exchange for external protons across cellular membranes 1. The protein contains a unique 14-transmembrane helix architecture, distinguishing it from other SLC9A/NHE family members that possess 13 transmembrane helices 21. NHA2 functions as a homodimer and utilizes proton gradients to maintain intracellular pH and sodium homeostasis 2. The protein exhibits broad tissue distribution and plays diverse physiological roles including insulin secretion, renal blood pressure regulation, and sperm motility 34. Clinically, SLC9B2 is associated with diabetes mellitus and essential hypertension in humans 23. The protein shows significant upregulation in polycystic kidney disease, where it promotes cyst development and correlates with disease severity 5. Additionally, SLC9B2 serves as a downstream target of Brd4 in osteoclast differentiation, contributing to pathological bone loss in osteoporosis 6. The N-terminal region appears to have an auto-inhibitory function that regulates transport activity 7. Structure-based drug design approaches targeting NHA2, including the inhibitor phloretin, offer potential therapeutic strategies for related diseases 1.