SLC4A4 (NBCe1) is an electrogenic sodium/bicarbonate cotransporter that mediates bicarbonate transport across the plasma membrane with Na⁺:HCO₃⁻ stoichiometry of 1:2 to 1:3 1. It functions primarily in regulating intracellular pH and transepithelial acid-base homeostasis by facilitating bicarbonate influx/efflux at the basolateral membrane 2. In epithelial tissues, SLC4A4 participates in transcellular acid-base transport and pH control, while in non-epithelial tissues it contributes to diverse functions including neuronal activity and vascular regulation 1. In pancreatic islets, SLC4A4 mediates anion efflux coupled with insulin secretion 3. Disease relevance extends beyond the classical proximal renal tubular acidosis-ocular anomaly syndrome to emerging oncological roles. SLC4A4 serves as a driver of enzalutamide resistance in prostate cancer through NF-κB/STAT3-mediated P53 lactylation 4, while upregulation promotes immune responses in lung adenocarcinoma 5. Conversely, SLC4A4 is downregulated in colorectal cancer through miRNA-mediated suppression 6. Astrocytic SLC4A4 maintains blood-brain barrier integrity via CCL2-CCR2 pathway regulation; its loss exacerbates stroke-induced BBB disruption 7. These findings suggest SLC4A4 has multifaceted roles in pH homeostasis, immune function, and CNS pathology, with emerging therapeutic potential across multiple disease contexts.