Monoacetyldiacylglycerols as emerging immunomodulatory lipids in chronic inflammation: mechanisms, biology, and translational potential.

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.