Endothelin Receptor Antagonism in Sickle Cell Disease: Is the Time Now?

Sickle cell disease (SCD) is a severe heritable hemoglobinopathy characterized by chronic hemolysis, episodic vaso-occlusion, and progressive multi-organ damage. Although hydroxyurea remains the most established disease-modifying therapy and that newer approaches such as L-glutamine, voxelotor, crizanlizumab, and gene therapy have expanded the therapeutic landscape, important limitations remain. These include incomplete efficacy, recent clinical or regulatory setbacks, as well as high cost and access barriers. Thus, safe, accessible, and mechanistically targeted treatments remain urgently needed, particularly for patients with progressive end-organ injury. Mounting evidence implicates the peptide endothelin-1 (ET-1) as a mediator of SCD pathology, and blockade of one of its primary receptors, endothelin receptor A (ETA), may ameliorate several adverse effects. In humanized SCD mice, selective ETA antagonism provides robust nephroprotection, while Phase I clinical data suggest a favorable safety profile in addition to signals of improved albuminuria and vascular function. In parallel, selective ETA antagonists have rapidly advanced owing to multiple FDA approvals for proteinuric kidney diseases outside the context of SCD, in addition to approvals as antihypertensives. Here, we highlight emerging evidence supporting endothelin pathway blockade as a potential targeted therapy for complications such as sickle cell nephropathy, vasculopathy, and pain, while discussing key considerations for future trials.