NHE1 in Gastrointestinal Inflammation and Cancer: A Double-Edged Regulator

Na⁺/H⁺ exchanger 1 (NHE1), encoded by SLC9A1, is a widely expressed plasma membrane transporter that exchanges intracellular H⁺ for extracellular Na⁺ and plays a central role in intracellular pH regulation. Beyond ion transport, NHE1 also functions as a membrane-associated regulatory platform involved in cell volume control, cytoskeletal organization, migration, and stress adaptation. In the digestive system, these functions are closely related to epithelial homeostasis, inflammation, fibrosis, tumor progression, and therapeutic response. This review summarizes current evidence on the diverse roles of NHE1 in digestive diseases.

A narrative review of the current literature was conducted, focusing on three major aspects of NHE1 biology: molecular regulation and basic cellular functions, inflammatory and fibrotic remodeling, and digestive cancer biology.

Under physiological conditions or during acute injury, NHE1-mediated pH regulation helps epithelial cells adapt to acid-base stress, maintain barrier integrity, and support mucosal repair. In chronic disease, however, sustained or dysregulated NHE1 activity may contribute to persistent inflammation, stromal remodeling, and pathological tissue repair. In digestive cancers, NHE1 has mainly been studied for its role in tumor pH regulation. By promoting intracellular alkalinization and extracellular acidification, NHE1 can favor tumor cell survival, migration, invasion, extracellular matrix interactions, and resistance to anticancer treatment. However, its role is not uniformly tumor-promoting. In some digestive tumors, reduced NHE1 expression or activity is associated with more aggressive disease, suggesting that NHE1 may also contribute to epithelial homeostasis, differentiation, or growth control under specific conditions.

Taken together, the effects of NHE1 in digestive diseases are highly context dependent. Appropriate NHE1-mediated pH regulation can support epithelial adaptation and tissue repair, whereas sustained or dysregulated activity may promote chronic inflammation, fibrosis, and tumor progression. The observation that reduced NHE1 activity may also be unfavorable in certain tumors further highlights the importance of disease context, cell type, and microenvironment. A better understanding of these context-dependent effects may help guide the development of more selective NHE1-based biomarkers and therapeutic strategies.