Natural products targeting NLRP3 inflammasome for metabolic dysfunction-associated fatty liver disease: The known unknowns

Metabolic dysfunction-associated fatty liver disease (MAFLD), driven by fatty acid overload, secondary chronic inflammation, and fibrosis, has emerged as the most common chronic liver disease worldwide. There is no efficient pharmacotherapy for MAFLD nevertheless restraining the inflammatory reaction is recognized as a promising scheme for limiting the transition from steatosis to severe steatohepatitis. NLRP3 inflammasome, which senses endogenous danger and stress signals, has emerged as a rising horizon for inflammatory disease while transcriptional inactivation of NLRP3 inflammasome components revealing targeted inhibition of NLRP3 inflammasome is beneficial for MAFLD. This is also confirmed by the natural products targeting NLRP3 inflammasome activation who have shown potential efficacy in MAFLD therapy. This review summarizes the current knowledge of NLRP3 inflammasome activation and therapeutic drug targets for NLRP3 homeostasis. Accordingly, natural products reported to inhibit NLRP3 inflammasome for MAFLD improvement are summarized and classified based on their mechanism of action. We also listed the limitations and future directions for natural products targeting NLRP3 inflammasome in improving MAFLD treatment. Overall, a deep understanding of signals and mechanisms of NLRP3 inflammasome activation in MAFLD and the discovery of new natural products with the support of mechanistic research will be of great significance for MAFLD.