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In this study, we evaluated Dehydrozingerone\u201015, a novel dehydrozingerone derivative, for its anti\u2010inflammatory and antioxidant properties through standardised in\u00a0vitro and in\u00a0vivo approaches. Dehydrozingerone\u201015 suppressed the stimulatory effect of LPS in RAW 264.7 cells by reducing the secretion of interleukin\u20106 (IL\u20106), tumour necrosis factor\u2010alpha (TNF\u2010\u03b1), interleukin\u20101 beta (IL\u20101\u03b2), interleukin\u20102 (IL\u20102) and nitric oxide. Western blot analysis at the mechanistic level showed a reduced expression level of nitric oxide synthase (iNOS), I\u03baB kinase beta (Ikk\u2010\u03b2) and nuclear factor kappa\u2010B (NF\u2010\u03baB\/p65). Confocal microscopy studies further demonstrated that Dehydrozingerone\u201015 reduced the expression of NF\u2010\u03baB\/p65 markedly. In the in\u00a0vivo LPS\u2010induced sepsis model, Dehydrozingerone\u201015 administration reduced TNF\u2010\u03b1 and IL\u20106 expression and protected vital organs (lungs, kidneys, and liver) from acute inflammation. The anti\u2010inflammatory potential of Dehydrozingerone\u201015 was further validated in leukocyte migration induced by carrageenan and vascular permeability triggered by acetic acid assays, both of which showed significant inhibition. Pharmacokinetic analysis revealed that Dehydrozingerone\u201015 was rapidly absorbed in BALB\/c mice, reaching a <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> of 10\u2009349\u2009ng\/mL at 0.25\u2009h. The total drug exposure (AUC<jats:sub>0\u2013\u03b1<\/jats:sub>) was 13\u2009862\u2009ng.h\/mL, indicating sustained exposure, with high tissue distribution (20\u2009L\/kg) and moderate clearance. Additionally, toxicological evaluation at doses up to 2000\u2009mg\/kg body weight showed no significant alterations in haematological parameters compared with the vehicle control. Furthermore, based on a comparative evaluation of in\u00a0vitro and in\u00a0vivo results, Dehydrozingerone\u201015, relative to its parent molecule, demonstrates significant therapeutic potential with high efficacy against inflammation and oxidative stress.<\/jats:p>","DOI":"10.1111\/1440-1681.70063","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T07:10:33Z","timestamp":1754464233000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Novel Semisynthetic Derivative of Dehydrozingerone (<scp>DHZ<\/scp>\u201015) Modulates Lipopolysaccharide\u2010Stimulated Macrophages by Targeting the <scp>NF<\/scp>\u2010<scp>\u03baB<\/scp>\/p65 Pathway and In\u00a0Vivo Evaluation in a Sepsis <scp>BALB<\/scp>\/c Model"],"prefix":"10.1111","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1656-033X","authenticated-orcid":false,"given":"Irfan","family":"Qasam","sequence":"first","affiliation":[{"name":"CSIR\u2010Indian Institute of Integrative Medicine  Jammu India"},{"name":"Mutagenicity Laboratory, Pharmacology Division CSIR\u2010Indian Institute of Integrative Medicine  Jammu India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  Ghaziabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shah","family":"Nawaz","sequence":"additional","affiliation":[{"name":"CSIR\u2010Indian Institute of Integrative Medicine  Jammu India"},{"name":"Mutagenicity Laboratory, Pharmacology Division CSIR\u2010Indian Institute of Integrative Medicine  Jammu India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  Ghaziabad 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