{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:55:35Z","timestamp":1791374135897,"version":"4.3.1"},"reference-count":116,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Chronic inflammatory diseases remain a major global health burden, with approximately 30\u201340% of patients responding inadequately to current cytokine-targeted biologics, Janus kinase (JAK) inhibitors, or small-molecule immunomodulators. Beyond suboptimal efficacy, these therapies carry well-documented adverse effects, including infection and malignancy risks associated with JAK inhibitors, and act on single molecular targets, leaving upstream, membrane-proximal drivers of chronic inflammation largely unaddressed. Monoacetyldiacylglycerols (MacDGs), a structurally distinct class of partially acetylated triglycerides, have emerged as promising immunomodulatory lipids that act concurrently across multiple inflammatory signaling nodes, including STAT3\/STAT6 and NF-\u03baB pathways, macrophage polarization, and epithelial barrier integrity, offering mechanistic breadth that single-target therapies do not provide. Current evidence, derived predominantly from the synthetic analog palmitic\u2013linoleic\u2013acetyldiacylglycero (PLAG), demonstrates reproducible suppression of signal transducer and activator of transcription 3\/6 (STAT3\/STAT6) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB) signaling, rebalancing of Th17\/regulatory T cell (Treg) dynamics, context-dependent control of neutrophil activity, and stabilization of epithelial barriers under inflammatory stress across\n                    <jats:italic>in vitro<\/jats:italic>\n                    systems,\n                    <jats:italic>in vivo<\/jats:italic>\n                    models, and early clinical studies. By integrating these convergent effects across immune and epithelial compartments, this review frames MacDGs as a coherent class of membrane-proximal immunomodulatory lipids. Despite these advances, major uncertainties remain regarding endogenous biosynthesis, molecular targets, pharmacokinetics, metabolic fate, and structure\u2013activity relationships. As the first integrated synthesis to frame MacDGs as a coherent immunomodulatory lipid class rather than isolated experimental agents, this review consolidates foundational chemistry, biological occurrence, mechanistic insights, therapeutic applications, and translational challenges, offering a critical assessment of both the promise and substantial uncertainties that define this emerging field.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1927836","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:30:21Z","timestamp":1791372621000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Monoacetyldiacylglycerols as emerging immunomodulatory lipids in chronic inflammation: mechanisms, biology, and translational potential"],"prefix":"10.3389","volume":"17","author":[{"given":"Charles F.","family":"Manful","sequence":"first","affiliation":[{"name":"School of Science and the Environment, Memorial University of Newfoundland","place":["Corner Brook, NL, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dasinaa","family":"Subramaniam","sequence":"additional","affiliation":[{"name":"School of Science and the Environment, Memorial University of Newfoundland","place":["Corner Brook, NL, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Fordjour","sequence":"additional","affiliation":[{"name":"Biotron Experimental Climate Change Research Centre\/Department of Biology, University of Western Ontario","place":["London, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lord","family":"Abbey","sequence":"additional","affiliation":[{"name":"Department of Plant, Food and Environmental Sciences, Dalhousie University","place":["Truro, NS, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Thomas","sequence":"additional","affiliation":[{"name":"Biotron Experimental Climate Change Research Centre\/Department of Biology, University of Western Ontario","place":["London, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2024.103331","article-title":"Efficacy and safety of advanced combination treatment in immune-mediated inflammatory disease: A systematic review and meta-analysis of randomized controlled trials","volume":"149","author":"Solitano","year":"2024","journal-title":"J Autoimmun"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0675-0","article-title":"Chronic inflammation in the etiology of disease across the life span","volume":"25","author":"Furman","year":"2019","journal-title":"Nat 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