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This study identifies P-selectin as a pivotal regulator of HSC function under aging and inflammatory stress. We observed pronounced\n                    <jats:italic>Selp<\/jats:italic>\n                    upregulation in aged HSC and inflammatory contexts, which drives excessive proliferation and differentiation while depleting their long-term self-renewal capacity. Using tissue-specific\n                    <jats:italic>Selp<\/jats:italic>\n                    overexpression models, we demonstrate that chronic\n                    <jats:italic>Selp<\/jats:italic>\n                    elevation disrupts HSC polarity, promotes oxidative stress accumulation, and induces genomic instability. Over time, sustained\n                    <jats:italic>Selp<\/jats:italic>\n                    expression leading to LT-HSC exhaustion and impaired hematopoietic reconstitution. Single-cell transcriptomics revealed that\n                    <jats:italic>Selp<\/jats:italic>\n                    enforces a pro-inflammatory transcriptional program in HSC, hyperactivating IFN-\u03b3 and PI3K-AKT-MOTR signaling pathways. Mechanistically, P-selectin directly interacted with IFN\u03b3R1 on the HSC surface, which driving activation of JAK1-STAT1 and PI3K-AKT-mTOR signaling axes. Notably,\n                    <jats:italic>Selp<\/jats:italic>\n                    overexpression suppresses the pathogenic capacity of leukemia stem cells (LSC), highlighting potential therapeutic implications. Our findings established P-selectin as a molecular nexus linking chronic inflammation and aging to hematopoietic decline, with dual therapeutic implications: targeting P-selectin may mitigate age-related hematopoietic dysfunction while offering a strategy to selectively impair LSC activity in malignancies.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08050-9","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T13:09:20Z","timestamp":1761052160000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["P-selectin overexpression impairs hematopoietic stem cell homeostasis via inflammatory receptor-mediated proliferation and differentiation"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8522-4051","authenticated-orcid":false,"given":"Wei","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huandi","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunyu","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bochuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3973-2140","authenticated-orcid":false,"given":"Yiguo","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"8050_CR1","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1182\/blood-2017-06-746412","volume":"131","author":"G de Haan","year":"2018","unstructured":"de Haan G, Lazare SS. 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