Waltl, L.; Speck, K.; Wildermuth, R.; Haut, F.-L.; Permann, S.; D'Avino, D.; Cerqua, I.; Siller, A.; Schennach, H.; Rossi, A.; Magauer, T.; Koeberle, A.

Lipidomics-guided screening of unexplored chemical space in natural products provides access to small molecules capable of modifying cellular lipid profiles on a global scale. Here, we show that the meroterpenoid cyclosmenospongine from Spongia sp. shapes the lipid profile of immune cells, favoring anti-inflammatory and pro-resolving over pro-inflammatory lipid mediators. Structural variation revealed derivatives that inhibit leukotriene biosynthesis to varying extents while differentially upregulating pro-resolving lipid mediators, epoxyeicosatrienoic acids, endocannabinoids, and sphingosine-1-phosphate, along with other mediators, both in resting and activated innate immune cells in vitro and in self-resolving murine peritonitis in vivo. Mechanistically, meroterpenoids target 5-lipoxygenase or 5-lipoxygenase-activating protein, promote the translocation of 15-lipoxygenase-1 to cytoplasmatic sites, and inhibit monoacylglycerol lipase. They also redirect arachidonic acid (AA) from neutral lipids to specific phospholipids, while increasing the total concentration of free AA. Furthermore, meroterpenoids reprogram lipid metabolism in immune cells, decreasing the levels of neutral lipids, triacylglycerols, and cholesteryl esters. This shift correlates with a reduced capacity for leukotriene biosynthesis and is mimicked by the inhibition of sterol-O-acyltransferase and diacylglycerol acyltransferase-1/2. In conclusion, specific meroterpenoids exert anti-inflammatory effects by intervening in lipid mediator biosynthesis, prompting structure-controlled switches in lipid mediator classes, among others, through an unexpected link between lipogenesis and inflammation.