Hao-zhan Qu, Xiuqi Wang
Abstract BEST4⁺ cells are a recently identified, functionally specialized intestinal epithelial cell population characterized through single-cell and spatial transcriptomic analyses in humans, pigs, rats, and other vertebrates. These cells characteristically express BEST4 , OTOP2 , CA7 , and GUCY2C , and exhibit particularly high CFTR expression in the small intestine, supporting their roles in luminal pH sensing, fluid-electrolyte homeostasis, and mucus hydration. Emerging evidence from organoid and cross-species studies supports a predominant role for the NOTCH–SPIB signaling axis in driving BEST4⁺ cell differentiation, but their lineage identity and regulatory mechanisms remain incompletely resolved. This review focuses on intestinal epithelial BEST4⁺ cells as a critical cellular hub that connects ion transport physiology with the pathophysiology of secretory diarrhea. We summarize the molecular identity, regional distribution, and cross-species conservation of BEST4⁺ cells. We then evaluate their roles in luminal pH regulation, electrogenic fluid secretion, and mucus barrier integrity. We detail how bacterial enterotoxins activate the GC-C/cGMP/CFTR and cAMP/PKA/CFTR pathways in BEST4⁺ cells to drive pathological fluid hypersecretion, and discuss how viral infections may indirectly engage or amplify BEST4⁺ cell-associated ion-transport pathways. We also outline their relevance to viral diarrhea, inflammatory bowel disease, and cystic fibrosis-associated intestinal dysfunction. Finally, we assess established antidiarrheal approaches and investigational strategies that modulate BEST4⁺ cell-associated pathways, and emphasize the need for cell-type-specific validation in physiologically relevant in vivo models.