SLC9A3 encodes a plasma membrane Na+/H+ antiporter that exchanges intracellular H+ ions for extracellular Na+ in 1:1 stoichiometry, playing a critical role in salt and fluid absorption and pH homeostasis 1. As the major apical Na+/H+ exchanger in kidney and intestine, SLC9A3 is essential for renal and intestinal Na+ absorption and blood pressure regulation 23. The protein functions as part of neutral NaCl absorption through scaffolding complexes involving ezrin and PDZ domain-containing proteins 4. SLC9A3 is regulated by post-prandial digestion-related signals and controls intracellular pH homeostasis 4. Loss-of-function mutations cause congenital diarrhea characterized by secretory sodium loss 5, while SLC9A3 deficiency has been associated with congenital bilateral absence of the vas deferens (CBAVD) through interaction with CFTR 67. SLC9A3 variants modulate cystic fibrosis lung disease severity and susceptibility to Pseudomonas aeruginosa infection, with the T allele of rs4957061 associated with earlier infection acquisition and reduced lung function 8. SLC9A3 deficiency causes progressive lower urinary tract dysfunction through electrolyte imbalance-induced bladder inflammation and fibrosis 9. The selective NHE3 inhibitor tenapanor was approved for irritable bowel syndrome treatment and hyperphosphatemia management 510.