摘要Background:Activation of NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)inflammasomes induced by pyroptosis is crucial in metabolic dysfunction-associated steatohepatitis(MASH)progression.Adiponectin possesses an anti-inflammatory role in various liver diseases.This study aimed to evaluate the effects of adiponectin on MASH.Methods:Adiponectin-mediated anti-inflammatory mechanisms,effects on pyroptosis-related proteins,and activation of NLRP3 inflammasomes were investigated using methionine-choline-deficient(MCD)-induced MASH murine model and in vitro models.The degree of MASH inflammation in liver tissue of C57BL/6J mice was assessed using histopathology.Enzyme-linked immunosorbent assay was performed to measure levels of inflammatory factors[interleukin-18(IL-18),IL-1β,and tumor necrosis factor-α(TNF-α)]in mice serum and culture medium.Western blot and quantitative polymerase chain reaction were performed to analyze the expression of pyroptosis-related genes and proteins in liver tissues of mouse model and in vitro models.Macrophage recruitment in vitro was evaluated using co-culture of upper and lower chambers.Results:MASH developed in MCD diet mice[metabolic dysfunction-associated steatotic liver disease(MASLD)activity score=6]but not in methionine-choline-sufficient(MCS)diet mice(MASLD activity score=3).Compared to MCS-fed mice,MCD-fed mice showed increased serum levels of aspartate amino-transferase,IL-18,IL-1β,and TNF-α and higher MASLD activity score(P＜0.001).Adiponectin inhibited these increases(P＜0.05)and suppressed mRNA and protein levels of NLRP3,gasdermin-D(GSDMD),and GSDMD-N in liver tissues(P＜0.05).In vitro,lipopolysaccharide(LPS)/palmitic acid(PA)increased the levels of IL-18,IL-1β,and TNF-α,mRNA expressions of CASP1 and GSDMD,and production of CASP1,NLRP3,GSDMD,and GSDMD-N(P＜0.01).Adiponectin reduced the levels of these inflammatory fac-tors and downregulated the mRNA expression and protein generation of pyroptosis-related markers(P＜0.05).HepG2 cells pretreated with LPS/PA recruited more J774A.1 cells(P＜0.001)and increased inflam-matory factor secretion by J774A.1 cells(P＜0.001).Adiponectin inhibited this recruitment and reduced inflammatory factor secretion(P＜0.001).Conclusions:Adiponectin inhibits hepatocyte pyroptosis by reducing the production and activation of NLRP3 inflammasomes,CASP1,and GSDMD,thus improving the inflammatory response in MASH and possibly delaying or reversing MASLD progression.