Slc9a8, encoding the sodium/hydrogen ion exchange protein NHE8, is an integral membrane protein in the SLC9 gene family. It catalyzes the electroneutral exchange of Na+ and H+ down their respective concentration gradients, crucial for physiological processes like intracellular pH and cell volume regulation, as well as systemic electrolyte and fluid volume homeostasis [4].

In mice, Slc9a8 knockout leads to retinal defects due to retinal pigmented epithelium (RPE) dysfunction. The mutant retinas show photoreceptor separation from the RPE, macrophage infiltration, and abnormal RPE morphology. NHE8 protein localizes to endosomes, and mutant cells have smaller recycling endosomes, indicating its role in maintaining endosomal volume and/or pH for RPE integrity and function [2].

In colitis mouse models, compromised NHE8 expression due to vitamin D-deficiency or VDR knockout leads to more serious mucosal damage, suggesting its importance in intestinal barrier protection [3].

In colorectal cancer cells, downregulation of SLC9A8 promotes epithelial-mesenchymal transition (EMT) and metastasis via the IL6-JAK1/STAT3 signaling pathway, with implications for its potential as a therapeutic target [1].

In summary, Slc9a8 is essential for maintaining normal physiological functions in the retina and intestine. Mouse models with Slc9a8 knockout or knockdown have revealed its significance in retinal integrity and in preventing the progression of colitis and colorectal cancer metastasis. These findings highlight the importance of Slc9a8 in understanding the mechanisms of related diseases and developing potential treatments.