In conclusion, we dissect a nuclear interaction of β-arr1 in mediating ET-1/ETAR-induced HIF-1α responses, showing that nuclear β-arr1-mediated regulatory complex could represent a barcode required to enhance the transcription of specific target genes that orchestrate the intricate autocrine and paracrine ET-1/ETAR signalling network and interaction with tumor microenvironment. Here, EDN1 is linked to neoplasm.