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This study aimed to elucidate the role of the SREBP2-cholesterol biosynthetic pathway in M2 activation of interstitial macrophages (IMs) during allergic asthma. We observed a significant expansion of M2-polarized IMs with heightened SREBP2-cholesterol biosynthetic activity in the lungs of asthmatic mice. IL4, a key pro-allergic cytokine in allergic asthma, was found to induce SREBP2 maturation and activate the cholesterol biosynthetic signaling pathway in macrophages. Moreover, inhibiting SREBP2 maturation restrains IL4-induced M2 activation, both in vitro and in vivo. Intriguingly, this effect was independent of intracellular cholesterol levels; instead, cholesterol itself negatively regulated SREBP2 maturation and M2 activation. Mechanistically, mature SREBP2 transcriptional modulated IRF4 expression and interacted with it to promote IL4-induced M2 activation. Additionally, myeloid-specific\n                    <jats:italic>Scap<\/jats:italic>\n                    deficiency impeded the SREBP2 maturation process in macrophages, leading to reduced M2 activation and allergic airway inflammation. These findings highlight the pivotal role of the SREBP2-IRF4 axis in modulating M2 polarization of IMs and suggest potential therapeutic targets for asthma treatment.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08910-y","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T14:55:17Z","timestamp":1780498517000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["SREBP2 promotes macrophage alternative activation and allergic airway inflammation independent of cholesterol biosynthesis"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3351-4476","authenticated-orcid":false,"given":"Yinfang","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kua","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"LingLing","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1606-6696","authenticated-orcid":false,"given":"Shenwei","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9600-8266","authenticated-orcid":false,"given":"Yanping","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haipin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0226-331X","authenticated-orcid":false,"given":"Qingyu","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahuan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1770-8956","authenticated-orcid":false,"given":"Songmin","family":"Ying","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4390-7636","authenticated-orcid":false,"given":"Zhihua","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8981-8380","authenticated-orcid":false,"given":"Wen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"8910_CR1","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/s41590-018-0113-3","volume":"19","author":"GJ Koelwyn","year":"2018","unstructured":"Koelwyn GJ, Corr EM, Erbay E, Moore KJ. 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