Chalcone Derivatives From Abelmoschus manihot Seeds Restrain NLRP3 Inflammasome Assembly by Inhibiting ASC Oligomerization

Abstract

Three chalcone derivatives, abelmanihotols A-C <b>(1-3)</b>, and nine known compounds were isolated from <i>A. manihot</i> seeds, and their structures were determined using HRESIMS and NMR spectroscopic analysis. Compound <b>1</b> exhibited the most potent inhibitory effect (IC₅₀ = 4.79 ± 0.72 μM) against lipopolysaccharide (LPS)-induced NO release in THP-1 cells, and <b>s</b>ignificantly inhibited interleukin 1β (IL-1β) secretion, which is stimulated by LPS plus nigericin (IC₅₀ = 11.86 ± 1.20 μM), ATP or MSU, in THP-1 cells. A preliminary mechanism of action study indicated that compound <b>1</b> blocked the formation of nucleotide oligomerization domain-like receptor protein-3 (NLRP3) inflammasome formation by suppressing apoptosis-associated speck-like protein oligomerization, thereby attenuating caspase-1 activation and IL-1β release. These results reveal that compound <b>1</b> is not only a potent and efficacious NLRP3 inflammasome inhibitor but also a promising drug for the treatment of NLRP3-related diseases.