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Drugs","Marine Drugs"],"abstract":"<jats:p>Sulfated polysaccharides from red seaweeds are emerging as versatile bioactive macromolecules. Here, we report that funoran-type galactans from Gelidiopsis variabilis (GV) function as immunometabolic reprogrammers, orchestrating inflammation resolution through targeted remodeling of amino acid and fatty acid metabolism in macrophages, potentially via receptor-mediated pathways. Cold and hot water extraction yielded structurally distinct fractions (360\u20133006 kDa) characterized by NMR as sulfated galactans with \u03ba-carrageenan motifs and variable sulfation (6.6\u201321.5%). In RAW264.7 macrophages, fractions GV-1A and GV-2A induced an anti-inflammatory metabolic state characterized by arginine accumulation (from 4.61% to 7.06% of the total amino acid pool), reduced ornithine levels, and complete the elimination of pro-inflammatory myristate (14:0), while upregulating phagocytosis (149% of control). In a carrageenan-induced paw edema model, GV-1A and GV-2A dose-dependently upregulated pro-resolution markers (IL-10, IL-4, TGF-\u03b21, Arg1, HO-1), outperforming the standard drug meloxicam. While the in vitro arginine accumulation suggests functional arginase inhibition, the in vivo Arg1 upregulation reflects a transcriptional response in a complex tissue environment. We propose that these findings collectively support a \u2018resolution-phase metabolic phenotype\u2019, a working model whereby GV polysaccharides reprogram macrophage metabolism toward inflammation resolution through context-dependent mechanisms. These findings establish G. variabilis polysaccharides as metabolically active immunomodulators that promote inflammation resolution, with the potential for applications in inflammatory diseases and as a pharmaceutical platform for drug development.<\/jats:p>","DOI":"10.3390\/md24090299","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:47:13Z","timestamp":1787849233000},"page":"299","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Resolution-Phase Immunometabolic Reprogramming by Gelidiopsis variabilis Polysaccharides: Macrophage Polarization and In Vivo Anti-Inflammatory Efficacy"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9748-398X","authenticated-orcid":false,"given":"Amal D.","family":"Premarathna","sequence":"first","affiliation":[{"name":"School of Natural Sciences and Health, Tallinn University, Narva mnt 29, 10120 Tallinn, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4526-841X","authenticated-orcid":false,"given":"Katarzyna M.","family":"Dziubinska-Kuehn","sequence":"additional","affiliation":[{"name":"National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1480-3555","authenticated-orcid":false,"given":"Muthupandian","family":"Saravanan","sequence":"additional","affiliation":[{"name":"Prince Fahad bin Sultan Chair for Biomedical Research, University of Tabuk, Tabuk 71491, Saudi Arabia"},{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anti","family":"Soo\u00e4\u00e4r","sequence":"additional","affiliation":[{"name":"School of Natural Sciences and Health, Tallinn University, Narva mnt 29, 10120 Tallinn, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3278-7947","authenticated-orcid":false,"given":"Indrek","family":"Reile","sequence":"additional","affiliation":[{"name":"National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6922-6193","authenticated-orcid":false,"given":"Tamer A. 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