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Here, we investigated the dose- and time-dependent effects of CBD on circulating pro-inflammatory cytokines and the transcriptomic profiles of the liver and spleen in male C57BL\/6J mice. Animals received CBD intraperitoneally at 0.2, 10, or 20\u00a0mg\/kg body weight for either 2 days (short-term, ST) or 28 days (long-term, LT), with vehicle-treated controls. Serum IL-1\u03b2, IL-6, and TNF-\u03b1 were measured by ELISA, and RNA-Seq was performed on liver and spleen to characterize differential gene expression and enriched biological processes. CBD significantly reduced IL-1\u03b2 and TNF-\u03b1 after ST treatment across doses, whereas IL-6 decreased primarily during LT exposure, with the strongest reduction at day 14 and partial persistence to day 28 at higher doses. Transcriptomic responses were markedly organ- and regimen-dependent. The liver transcriptome exhibited pronounced, dose- and time-dependent remodeling, with the largest number of differentially expressed genes at 20\u00a0mg\/kg in ST and broad changes across doses in LT. The gene enrichment analyses indicated modulation of mitochondrial and translational pathways after ST high-dose exposure, lipid and fatty acid metabolism during LT, as well as circadian-associated regulation at higher-dose LT treatment, with innate immune\u2013associated signaling terms enriched at the highest dose. In contrast, the spleen displayed comparatively modest transcriptional changes, with limited differential expression in LT and a clearer response only after ST exposure to 20\u00a0mg\/kg, where altered genes showed trends related to lipid-associated processes. Together, these findings demonstrate that CBD attenuates circulating pro-inflammatory cytokines while inducing strong, dose- and time-dependent hepatic transcriptional reprogramming and relatively limited splenic transcriptomic shifts. The integration of systemic and organ-specific data supports a model in which CBD acts as a systemic immunometabolic modulator rather than a simple immunosuppressant.<\/jats:p>","DOI":"10.1007\/s00438-026-02525-w","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:08:17Z","timestamp":1790604497000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cannabidiol (CBD) differentially shapes systemic cytokines and transcriptomic profiles in the liver and spleen: insights from a male mouse model"],"prefix":"10.1007","volume":"301","author":[{"given":"Jakub","family":"\u017burowski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Oc\u0142o\u0144","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Jasielczuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Szmato\u0142a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Mizera-Szpilka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Semik-Gurgul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Sawicki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5979-144X","authenticated-orcid":false,"given":"Artur","family":"Gurgul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"2525_CR1","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders S, Pyl PT, Huber W (2015) HTSeq\u2014a Python framework to work with high-throughput sequencing data. 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