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This study investigated the biological activity of the dichloromethane extract of Maclura tinctoria leaves (DcMt), which was selected for further analyses after initial screening demonstrated superior antioxidant activity compared with the hexane extract (HxMt). Antioxidant capacity was evaluated by DPPH and FRAP assays, while cellular effects were assessed in RAW 264.7 macrophages through analyses of viability, cytokine gene expression, COX-2 modulation, catalase activity, and cell migration. LC-DAD-ESI-MS profiling revealed a well-defined chromatographic composition dominated by four major constituents, which were isolated and structurally elucidated by NMR and MS as prenylated flavonoids, several of which are reported here for the first time in M. tinctoria. DcMt exhibited strong antioxidant activity and preserved cell viability under oxidative stress, with optimal effects at 25 \u00b5g\/mL, accompanied by increased catalase activity. The extract modulated inflammatory markers by increasing IL-10 and IL-6 gene expression, maintaining IL-1\u03b2 levels, and regulating COX-2 expression. In addition, DcMt promoted macrophage migration, further supporting its potential role in modulating inflammatory responses. Importantly, all biological assays were performed using the crude extract, and the contribution of individual compounds remains to be further investigated. These findings support M. tinctoria as a promising source of bioactive compounds with antioxidant and immunomodulatory potential.<\/jats:p>","DOI":"10.3390\/ijms27125504","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T07:33:54Z","timestamp":1781768034000},"page":"5504","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Maclura tinctoria as a Modulator of Oxidative Stress and Inflammatory Responses"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8817-8067","authenticated-orcid":false,"given":"Eduarda Pires","family":"Costa","sequence":"first","affiliation":[{"name":"Department of General Biology, Federal University of Vi\u00e7osa, Vi\u00e7osa 36570-900, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2933-3732","authenticated-orcid":false,"given":"Allan Rodrigues","family":"Pires","sequence":"additional","affiliation":[{"name":"Department of General Biology, Federal University of Vi\u00e7osa, Vi\u00e7osa 36570-900, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1313-7877","authenticated-orcid":false,"given":"Mari\u00e1urea Matias","family":"Sarandy","sequence":"additional","affiliation":[{"name":"Department of Animal Biology, Federal University of Vi\u00e7osa, Vi\u00e7osa 36570-900, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3186-5328","authenticated-orcid":false,"given":"Romulo Dias","family":"Novaes","sequence":"additional","affiliation":[{"name":"Department of Structural Biology, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7330-051X","authenticated-orcid":false,"given":"Geraldo C\u00e9lio","family":"Brand\u00e3o","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Federal University of Ouro Preto, Ouro Preto 35400-000, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao Paulo Viana","family":"Leite","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Federal University of Vi\u00e7osa, Vi\u00e7osa 36570-900, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iorrana Vieira","family":"Salustiano","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Federal University of Vi\u00e7osa, Vi\u00e7osa 36570-900, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9689-7622","authenticated-orcid":false,"given":"Debora","family":"Esposito","sequence":"additional","affiliation":[{"name":"Plants for Human Health Institute, Animal Science, North Carolina Research Campus, North Carolina State University, Kannapolis, NC 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5831-3590","authenticated-orcid":false,"given":"Reggiani Vilela","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Department of Animal Biology, Federal University of Vi\u00e7osa, Vi\u00e7osa 36570-900, MG, Brazil"},{"name":"Plants for Human Health Institute, Animal Science, North Carolina Research Campus, North Carolina State University, Kannapolis, NC 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.phrs.2023.106733","article-title":"Current understanding of plant-derived exosome-like nanoparticles in regulating the inflammatory response and immune system microenvironment","volume":"190","author":"Yi","year":"2023","journal-title":"Pharmacol. 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