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Endothelial dysfunction plays a key role in PAH initiation and progression. Recent studies have implicated epigenetic dysregulation, particularly histone acetylation, as a key contributor to the transcriptional reprogramming underlying PAH. Among the histone acetyltransferases, EP300 catalyzes H3K27 acetylation and modulates transcriptional and metabolic programs in vascular cells. However, its specific role in endothelial dysfunction in PAH remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We investigated the role of EP300 in regulating transcriptional and functional responses in human pulmonary artery endothelial cells (PAECs) in PAH. Human and experimental PAH tissues showed increased EP300 expression and elevated H3K27ac levels. Pharmacological inhibition of EP300 in PAH-derived PAECs reduced global H3K27ac levels, oxidative stress, abnormal proliferation, and inflammatory responses. Transcriptomic analysis revealed that EP300 regulates gene networks related to inflammation, angiogenesis, and metabolism. Among these, neuropilin-1 (NRP1) has emerged as a direct EP300 target marked by H3K27ac enrichment in its regulatory regions. EP300 overexpression up-regulated NRP1 expression, whereas EP300 inhibition decreased NRP1 expression. Functional studies further demonstrated that NRP1 modulates VEGFR2 signaling and glycolytic gene expression. Notably, the pharmacological inhibition of NRP1 with EG00229 attenuated EP300-induced endothelial proliferation and oxidative stress in vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings identified EP300 as a central epigenetic regulator of endothelial dysfunction in PAH through H3K27ac-dependent activation of\n                      <jats:italic>NRP1<\/jats:italic>\n                      . The EP300-NRP1 axis integrates inflammatory, angiogenic, and metabolic signaling, contributing to endothelial dysfunction and disease onset. Targeting EP300-mediated histone acetylation may represent a promising therapeutic strategy for restoring endothelial homeostasis and slowing disease progression in patients with PAH.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-025-01386-0","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T15:22:02Z","timestamp":1765898522000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Epigenetic reprogramming drives endothelial dysfunction via neuropilin-1 in pulmonary hypertension"],"prefix":"10.1186","volume":"31","author":[{"given":"Maria T.","family":"Ochoa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine","family":"Leppert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Ricchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Rota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malik","family":"Bisserier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,16]]},"reference":[{"key":"1386_CR1","doi-asserted-by":"crossref","unstructured":"Bahi M, Li C, Wang G and Korman BD. 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This study used deidentified human lung tissue samples obtained from the Pulmonary Hypertension Breakthrough Initiative.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable. This study utilized deidentified human lung tissue samples obtained from the Pulmonary Hypertension Breakthrough Initiative (PHBI). All samples were collected with informed consent under protocols approved by the respective Institutional Review Boards (IRBs) of the participating institutions. As the data were deidentified and no individual-level information was presented, additional consent for publication was not needed.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"336"}}