1-O-acetylbritannilactone alleviates high-fat diet-induced fatty liver by covalently targeting NLRP3.

Abstract

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a global condition affecting approximately 30% of adults worldwide. Recent research has clarified the key role of the NLRP3 inflammasome in the pathogenesis of MASLD, particularly in liver fibrosis and lipid accumulation. This study aimed to screen natural products targeting the NLRP3 inflammasome and assess their protective effects on MASLD. METHODS: We screened an in-house natural product library to identify potential NLRP3 inhibitors by evaluating the effects of the candidates on inhibiting IL-1β release in bone marrow-derived macrophages (BMDMs) challenged with lipopolysaccharide (LPS) and palmitic acid (PA). The therapeutic effects of the potential candidate were determined in a high-fat diet-induced MASLD mouse model. RESULTS: 1-O-acetylbritannilactone (ABL) was found to inhibit NLRP3 inflammasome activation and NLRP3-mediated pyroptosis in BMDMs. Mechanistically, ABL covalently targeted NLRP3 at the Cys669 residue in the NLRP3 NACHT domain, thereby disrupting inflammasome assembly by selectively impeding the formation of the NLRP3-NEK7 complex. In vitro studies show that ABL exhibited an excellent inhibitory effect on lipid metabolism and liver fibrosis by restraining NLRP3 inflammasome activity. CONCLUSIONS: The study found that ABL mitigates MASLD in mice by inhibiting NLRP3 inflammasome, suggesting that ABL is an effective therapy for MASLD.