Pyroptosis is a form of programmed cell death initiated by inflammasomes and characterized by Caspase-1 activation and gasdermin D (GSDMD)-dependent pore formation, fueling liver inflammation and fibrosis. The activation of the NLRP3 inflammasome plays a pivotal role in driving these processes in Metabolic Dysfunction-Associated Steatohepatitis (MASH).Here, we tested the hypothesis that global deletion of GSDMD (GSDMDKO) provides protection against diet-induced MASH by attenuating inflammasome activation. This protective effect may reduce fibrogenesis through attenuated inflammasome activation and diminished bidirectional activation of resident liver cells within the inflammatory environment. Our work showed that GSDMD deletion protected the liver from pro-inflammatory cytokine expression and immune cell infiltration in response to a choline-deficient, amino acid-defined high-fat diet (CDAA-HF), thereby alleviating both steatosis and inflammation in MASH.

Additionally, GSDMDKO mice exhibited reduced hepatic fibrosis, revealing a critical role for GSDMD in regulating lipid metabolism, immune response, and fibrogenesis through modulation of HSC and myeloid cell activity. Notably, close interactions between monocytes, Kupffer cells (KCs), HSCs, and hepatocytes fostered a distinctive inflammatory microenvironment, characterized by the expulsion of monocyte extracellular traps (METs). The deletion of GSDMD shifted Kupffer cells from inflammatory mediators to central niche regulators, establishing a bidirectional crosstalk with HSCs and modulating their fibrogenic activity. Our findings highlight GSDMD as a central orchestrator of liver inflammation and fibrogenesis in MASH. These results underscore GSDMD's potential as a therapeutic target to disrupt the inflammatory cascade and fibrosis in liver disease.