NHE1-Mediated Metabolic Reprogramming in Cancer

The sodium-hydrogen exchanger-1 (NHE1) is a ubiquitously expressed transmembrane transporter that plays a central role in maintaining intracellular pH homeostasis and supporting normal cellular function. In cancer, NHE1 is overexpressed in many tumor types and has been associated with increased cancer cell metastasis and proliferation. Beyond these established roles, emerging evidence implicates NHE1 as a regulator of cancer cell metabolism. By driving intracellular alkalinization and shaping the tumor microenvironment, NHE1 influences metabolic pathway activity, mitochondrial function, redox balance, and cellular stress responses. In this review, we synthesize current evidence linking NHE1 dysregulation to metabolic reprogramming in cancer, with a focus on mitochondrial metabolism, glycolytic flux, lysosomal biology, and reactive oxygen species-associated stress pathways. We further evaluate pharmacological strategies targeting NHE1, emphasizing their metabolic consequences, translational potential, and the challenges that have limited clinical application to date. Collectively, this review highlights NHE1 as a potential integrator of ion transport and metabolic control in cancer and discusses how targeting NHE1-driven metabolic programs may support the development of novel therapeutic strategies.