Revising NHE‐1: From Cardiac Homeostasis to Heart Failure and Future Drug Development

ABSTRACT NHE‐1 is a Na + /H + exchanger that receives phosphorylation signals, binds calmodulin and responds to neurohormonal input from angiotensin II, endothelin‐1, and adrenergic pathways. In cardiac myocytes, NHE‐1 maintains pH homeostasis and couples to Na + /Ca 2+ exchange and mitochondrial ion handling. During heart disease sustained activation drives intracellular Na + accumulation, promoting Ca 2+ overload and mitochondrial dysfunction. Oxidative stress then creates amplifying cycles that activate signaling pathways resulting to arrhythmias and fibrosis. Clinical trials failed despite preclinical promise, due to a variety of false experimental factors. SGLT2 inhibitors appear to modulate NHE‐1 indirectly through metabolic reprogramming and hemodynamic effects rather than direct blockade. Current approaches use structural data to target regulatory sites and phosphorylation‐dependent conformational states instead of the transport pore. Translation to patients will require biomarkers identifying pathological hyperactivity and better patient stratification methods. Here, we try to review NHE‐1 structure, regulation, and physiology that may influence research on future drug development.