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