SLC9A5 (NHE5) is a plasma membrane Na+/H+ antiporter that mediates electroneutral exchange of intracellular H+ for extracellular Na+ in 1:1 stoichiometry, primarily regulating intracellular pH homeostasis in neural tissues 1. The gene is expressed in brain, testis, spleen, and skeletal muscle 1. Beyond pH regulation, SLC9A5 acts as a negative regulator of dendritic spine growth and participates in postsynaptic remodeling and signaling [UniProt]. It also contributes to organellar pH regulation with consequences for receptor tyrosine kinase trafficking. Clinically, SLC9A5 demonstrates oncogenic properties in colorectal cancer (CRC), where it is significantly upregulated in tumor tissues compared to adjacent normal tissue 2. SLC9A5 knockdown suppresses CRC cell proliferation, migration, and invasion, with mechanistic involvement in peroxisomal fatty acid oxidation pathways via ACOX1 regulation 2. In melanoma, SLC9A5 upregulation contributes to BRAF inhibitor resistance and promotes a mesenchymal-like phenotype associated with therapy resistance 3. Conversely, SLC9A5 expression is downregulated in loperamide-induced constipation, suggesting a role in colonic epithelial function 4. These findings position SLC9A5 as a therapeutic target in cancer and potentially relevant to gastrointestinal disorders.