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The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O\n                    <jats:sub>2<\/jats:sub>\n                    to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen\u2019s ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.\n                  <\/jats:p>","DOI":"10.7554\/elife.87496","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T15:07:11Z","timestamp":1684854431000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.87496","source":"Crossref","is-referenced-by-count":5,"title":["High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen"],"prefix":"10.7554","volume":"12","author":[{"given":"Wan-ping","family":"Yang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02afcvw97","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University","place":["Nantong, 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