Monoacetyldiacylglycerols as emerging immunomodulatory lipids in chronic inflammation: mechanisms, biology, and translational potential
- 1School of Science and the Environment, Memorial University of Newfoundland, Corner Brook, NL, Canada.
- 2Biotron Experimental Climate Change Research Centre/Department of Biology, University of Western Ontario, London, ON, Canada.
- 3Department of Plant, Food and Environmental Sciences, Dalhousie University, Truro, NS, Canada.
Abstract
Chronic inflammatory diseases remain a major global health burden, with approximately 30–40% 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-κB 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–linoleic–acetyldiacylglycero (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-κB) signaling, rebalancing of Th17/regulatory T cell (Treg) dynamics, context-dependent control of neutrophil activity, and stabilization of epithelial barriers under inflammatory stress across in vitro systems, in vivo 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–activity 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.
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BibTeX
@article{manful2026monoacetyldiacylglycerols,
title = {{Monoacetyldiacylglycerols as emerging immunomodulatory lipids in chronic inflammation: mechanisms, biology, and translational potential}},
author = {Charles F Manful and Dasinaa Subramaniam and Eric Fordjour and Lord Abbey and Raymond Thomas},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1927836},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1927836/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Monoacetyldiacylglycerols as emerging immunomodulatory lipids in chronic inflammation: mechanisms, biology, and translational potential
AU - Charles F Manful
AU - Dasinaa Subramaniam
AU - Eric Fordjour
AU - Lord Abbey
AU - Raymond Thomas
PY - 2026
DA - 2026/10/07
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1927836
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1927836/full
AB - Chronic inflammatory diseases remain a major global health burden, with approximately 30–40% 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-κB 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–linoleic–acetyldiacylglycero (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-κB) signaling, rebalancing of Th17/regulatory T cell (Treg) dynamics, context-dependent control of neutrophil activity, and stabilization of epithelial barriers under inflammatory stress across in vitro systems, in vivo 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–activity 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.
SN - 1664-3224
ER -