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Lenabasum activates two distinct receptors: CB2R and the nuclear peroxisome proliferator-activated receptor-\u03b3 (PPAR\u03b3). Our goal was to investigate the dominant mechanism of action leading to pathogenic IFN\u03b2 reduction by lenabasum (through CB2R or PPAR\u03b3) across leukocytes. We utilized whole blood leukocytes from 14 DM patients and grouped patients as in vitro responders or non-responders. We stimulated leukocytes in vitro in the presence of CB2R and PPAR\u03b3 inhibitors and lenabasum. Intracellular and extracellular marker expression was analyzed by flow cytometry. CD4<jats:sup>+<\/jats:sup> T (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009<jats:italic>0.05<\/jats:italic>), monocyte-derived dendritic cells (<jats:italic>p<\/jats:italic>\u2009=\u2009<jats:italic>0.06<\/jats:italic>), and intermediate monocytes (iMs) (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009<jats:italic>0.05<\/jats:italic>) activate a CB2R-mediated lenabasum pathway in responders. Responder B cells (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009<jats:italic>0.01<\/jats:italic>), CD8<jats:sup>+<\/jats:sup> T cells (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009<jats:italic>0.01<\/jats:italic>), and non-classical monocytes (<jats:italic>p<\/jats:italic>\u2009=\u2009<jats:italic>0.06<\/jats:italic>) activate a co-dependent CB2R\/PPAR\u03b3-mediated lenabasum pathway. Lenabasum can independently activate CB2R or PPAR\u03b3 in myeloid dendritic cells (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009<jats:italic>0.05<\/jats:italic>). Responder plasmacytoid dendritic cells (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009<jats:italic>0.05<\/jats:italic>) and classical monocytes (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009<jats:italic>0.01<\/jats:italic>) activate a PPAR\u03b3-mediated lenabasum pathway. CB2R was increased in certain responder CB2R-mediated cell populations compared to non-responders. Lenabasum elevated cyclooxygenase-2 or 15-lipoxygenase-1 levels in all responder CB2R-mediated cell populations except iMs. Baseline cell-to-cell CB2R\/PPAR\u03b3 testing could be useful to select ideal lenabasum candidates.<\/jats:p>\n          <jats:p>\n            <jats:bold>Trial Registration:<\/jats:bold> Registered at ClinicalTrials.gov (Identifier: NCT03813160) on 2019\u201301-23. Sponsored by Corbus Pharmaceuticals Inc.<\/jats:p>","DOI":"10.1038\/s41598-025-92001-z","type":"journal-article","created":{"date-parts":[[2025,5,18]],"date-time":"2025-05-18T04:33:21Z","timestamp":1747542801000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Diverse Lenabasum pathway activation in dermatomyositis patients\u2019 blood"],"prefix":"10.1038","volume":"15","clinical-trial-number":[{"clinical-trial-number":"nct03813160","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Nilesh","family":"Kodali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"DeAnna","family":"Diaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohan","family":"Dhiman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Vazquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Dan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Sprow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julianne","family":"Kleitsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meena","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Bashir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria P.","family":"Werth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,18]]},"reference":[{"issue":"5","key":"92001_CR1","doi-asserted-by":"publisher","first-page":"375","DOI":"10.4103\/0019-5154.100486","volume":"57","author":"D Fiorentino","year":"2012","unstructured":"Fiorentino, D., Marvi, U. & Chung, L. 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