{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HEY1 is a conserved basic helix‐loop‐helix transcription factor that functions as a canonical downstream effector of Notch signaling to modulate cell fate decisions, differentiation, and proliferation in multiple biological contexts. In endothelial cells, HEY1 expression is induced by signals transmitted through DLL4‐Notch and ALK1–SMAD pathways, thereby contributing to the repression of angiogenic cues—such as VEGF signaling—and promoting proper vascular remodeling by restricting tip cell formation and endothelial sprouting."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " In the cancer arena, elevated HEY1 levels have been linked to the maintenance of stem‐like properties and enhanced tumorigenesis. For instance, HEY1 is highly expressed in pancreatic cancer–initiating cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", and its activation downstream of the FRA1 pathway contributes to liver cancer stem cell expansion in hepatocellular carcinoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Similarly, in lung cancers, HEY1 is part of the transcriptional output of active Notch signaling associated with malignant phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, the identification of a recurrent HEY1–NCOA2 gene fusion in mesenchymal chondrosarcomas underscores an oncogenic role for HEY1 in specific sarcoma subtypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In addition to its roles in vascular and tumor biology, HEY1 is also pivotal in osteoblast differentiation; its induction by bone morphogenic protein 2 and Notch signaling acts to negatively regulate osteoblast maturation by antagonizing Runx2 activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Collectively, these studies reveal that HEY1 serves as a versatile transcriptional modulator operating downstream of Notch and intersecting pathways to regulate vascular remodeling, stem cell maintenance, tumor progression, and differentiation, thereby representing a potential diagnostic marker and therapeutic target in diverse human diseases.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nilay S Patel, Ji-Liang Li, Daniele Generali, et al. 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