Endothelin-1 production pathway (ET-1 pathway)

The Endothelin-1 (ET-1) production pathway is a multi-step biochemical process responsible for the synthesis of one of the most potent endogenous vasoconstrictors. The pathway begins with the transcription of the EDN1 gene into prepro-endothelin-1, which is subsequently cleaved by signal peptidases and furin-like convertases to form the inactive precursor, Big Endothelin-1. The final, rate-limiting step involves the conversion of Big ET-1 into the active 21-amino acid ET-1 peptide by the membrane-bound metalloprotease Endothelin-converting enzyme 1 (ECE-1). Once active, ET-1 signals through two G protein-coupled receptors, ETA and ETB, to regulate vascular tone, cell proliferation, and inflammatory responses. Overactivation of this pathway is strongly linked to the pathogenesis of pulmonary arterial hypertension (PAH), where elevated ET-1 levels drive chronic vasoconstriction and structural remodeling of the pulmonary vasculature. It is also implicated in systemic hypertension, chronic kidney disease, and various cancers where it promotes tumor cell survival and angiogenesis. Therapeutic strategies targeting this pathway primarily involve endothelin receptor antagonists (ERAs) like bosentan and ambrisentan, which block the downstream effects of the peptide. Although ECE-1 inhibitors have been developed to block the production of ET-1 at its source, they are less commonly used in clinical practice than receptor-focused therapies. Key safety considerations for drugs modulating this pathway include potential liver injury, fluid retention, and significant teratogenic risks.

Other names

Endothelin systemET-1 synthesis pathwayBig ET-1 to ET-1 conversionEndothelin signaling pathway

Endothelin receptor antagonism (ETA and/or ETB); Endothelin-converting enzyme inhibition