Tetracyclic β-Acid Meroterpenoids as Potent Anti-neuroinflammatory Agents via NLRP3 Inflammasome

Three pairs of novel β-acid meroterpenoid enantiomers with an unprecedented 5/6/7/5 tetracyclic ring skeleton, (±)-humulunones A-C (<b>1</b>-<b>3</b>), were isolated from <i>Humulus lupulus</i> L. Their structures were elucidated by comprehensive spectroscopic data analysis, calculated NMR and electronic circular dichroism, and X-ray single-crystal diffraction. Compounds (+)-<b>1</b>, (-)-<b>1</b>, (+)-<b>2</b>, and (-)-<b>2</b> exhibited significant anti-neuroinflammatory effects on LPS-induced BV2 cells. Furthermore, compound (-)-<b>1</b> effectively ameliorated oxidative stress and inhibited NLRP3 inflammasome activation, demonstrating efficacy comparable to that of the classic inhibitor MCC950 in suppressing the expression of NLRP3, ASC, caspase-1, and downstream inflammatory factors. Molecular docking and a cellular thermal shift assay implied that (-)-<b>1</b> exerted its anti-neuroinflammatory effect through potential interaction with the NLRP3 protein, which provided a fresh perspective for the drug development of neuroinflammatory-related diseases.