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Emerging evidence suggests that macrophages are essential for sarcoid granuloma initiation. Legumain (LGMN), a cysteine protease, regulates macrophage polarization in various cancers. However, its involvement in sarcoid granuloma formation remains elusive. Herein, LGMN is upregulated in macrophages within sarcoid\u2010like granulomas. Genetic deletion of\n                    <jats:italic>Lgmn<\/jats:italic>\n                    exacerbates granulomatous inflammation in a\n                    <jats:italic>Propionibacterium acnes<\/jats:italic>\n                    (\n                    <jats:italic>P. acnes<\/jats:italic>\n                    )\u2010induced mouse model, accompanied by increased M1 macrophage polarization. Mechanistically, LGMN binds to integrin \u03b1v\u03b23 on the macrophage surface and restrains M1 polarization by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1)\/signal transducer and activator of transcription 1 (STAT1) pathway. Furthermore, intratracheal administration of lipid nanoparticles carrying\n                    <jats:italic>Lgmn<\/jats:italic>\n                    plasmid DNA effectively alleviates granuloma formation induced by\n                    <jats:italic>P. acnes<\/jats:italic>\n                    or trehalose 6,6'\u2010dimycolate, concomitant with decreased mTORC1\/STAT1 activation and M1 polarization. These findings reveal the pivotal role of LGMN in restraining sarcoid granulomatous inflammation through suppression of mTORC1\/STAT1\u2010driven M1 macrophage polarization. Therefore, LGMN supplementation may be a promising therapeutic strategy for sarcoidosis.\n                  <\/jats:p>","DOI":"10.1002\/advs.202520635","type":"journal-article","created":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T05:52:10Z","timestamp":1775281930000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Legumain Restrains Granuloma Formation by Inhibiting mTORC1\/STAT1\u2010Mediated M1 Macrophage Polarization in Sarcoidosis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9833-7547","authenticated-orcid":false,"given":"Mengyuan","family":"Liu","sequence":"first","affiliation":[{"name":"China\u2010Japan Friendship Hospital (Institute of Clinical Medical Sciences) Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"},{"name":"National Center for Respiratory Medicine State Key Laboratory of Respiratory Health and Multimorbidity 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