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While lineage-determining transcription factors establish myeloid identity, our understanding of the transcriptional regulation of myeloid cell behavior in chronic inflammatory contexts remains limited. Nuclear factor-Y (NF-Y) is a trimeric CCAAT-binding transcription factor that regulates cell proliferation and differentiation and is essential for maintaining stem and progenitor cell fitness. Here, we investigate NF-Y activity in myeloid cell function and survival using integrated single-cell transcriptomics and myeloid-specific deletion of the NF-YA subunit. At RNA level, NF-Y subunit transcripts were detected across myeloid compartments, with NF-YA enriched in proliferative macrophages and immature neutrophils. In mouse atherosclerotic lesions, low NF-YA levels were associated with macrophages exhibiting lipid-handling and phagocytic signatures and with neutrophils displaying a proinflammatory phenotype. NF-Y deficiency impaired neutrophil adhesion and rolling, increased their susceptibility to apoptosis, and promoted activation and lipid accumulation in macrophages. In vivo, myeloid NF-YA deficiency reduced circulating neutrophil counts, increased macrophage and neutrophil apoptosis during acute inflammation, expanded necrotic cores, leading to larger and more unstable atherosclerotic lesions, and aggravated both atherosclerosis and injury-induced neointimal thickening. These findings identify NF-Y as a transcriptional safeguard of myeloid cell survival during inflammatory stress, thereby shaping disease progression and outcomes in vascular disease.<\/jats:p>","DOI":"10.1093\/jleuko\/qiag113","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T11:13:30Z","timestamp":1786706010000},"source":"Crossref","is-referenced-by-count":0,"title":["The transcription factor NF-Y promotes myeloid cell survival and protects from inflammatory vascular disease"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1169-7475","authenticated-orcid":false,"given":"Carlos","family":"Silvestre-Roig","sequence":"first","affiliation":[{"name":"Institute of Experimental Pathology, Center for Molecular Biology of Inflammation (ZMBE), University of M\u00fcnster , Von Esmarch Stra\u00dfe 56, M\u00fcnster 48149 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 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Stra\u00dfe 56, M\u00fcnster 48149 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7254-9611","authenticated-orcid":false,"given":"Eva","family":"Gricar","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University of M\u00fcnster , R\u00f6ntgenstra\u00dfe 21, M\u00fcnster 48149 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8811-8369","authenticated-orcid":false,"given":"Pilar","family":"Gonzalo","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBER-CV) , Instituto de Saludo Carlos III (ISCIII), Calle Monforte de Lemos 3-5, Madrid 28029 ,","place":["Spain"]},{"name":"Centro Nacional de Investigaciones Cardiovasculares (CNIC) , Melchor Fern\u00e1ndez Almagro 3, Madrid 28029 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