Reorganization of Innate Immune Cell Lipid Profiles by Bioinspired Meroterpenoids to Limit Inflammation

Lipidomics-guided screening of unexplored natural product chemical space provides access to small molecules that globally reprogram cellular lipid profiles. Here, we show that the meroterpenoid cyclosmenospongine from Spongia sp. reshapes immune cell lipidomes, shifting them from pro-inflammatory toward anti-inflammatory and pro-resolving mediators. Structural variation yielded derivatives that context-dependently inhibit leukotriene biosynthesis to varying extents while upregulating pro-resolving lipid mediators, epoxyeicosatrienoic acids, endocannabinoids, sphingosine-1-phosphate, and others in resting and activated innate immune cells in vitro, as well as in self-resolving murine peritonitis and fibrosis in vivo. Mechanistically, meroterpenoids target 5-lipoxygenase or 5-lipoxygenase-activating protein, promote 15-lipoxygenase-1 translocation to particulate sites, and inhibit monoacylglycerol lipase. They also redirect arachidonic acid from neutral lipids to specific phospholipids while increasing free arachidonic acid levels. Furthermore, meroterpenoids reprogram immune cell lipid metabolism by reducing neutral lipid, triacylglycerol, and cholesteryl ester levels, a shift that correlates with a lower capacity for leukotriene biosynthesis and is phenocopied by inhibiting sterol-O-acyltransferase, which catalyzes cholesterol esterification for storage, and diacylglycerol acyltransferase-1/2, which catalyze the final step in triacylglycerol biosynthesis. In conclusion, specific meroterpenoids exert anti-inflammatory effects by rewiring lipid mediator biosynthesis through structure-controlled switches in lipid mediator classes, and an unexpected link between lipogenesis and inflammation.