Fetuin B drives metabolism-associated steatohepatitis by promoting hepatocyte pyroptosis via NLRP3/GSDMD pathway

Hepatocyte pyroptosis critically contributes to metabolism-associated fatty liver disease (MAFLD) progression. Fetuin-B (FETUB), a hepatocytokine, promotes pyroptosis by downregulating adiponectin receptor 1 (AdipoR1), thereby activating the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome/GSDMD pathway. This study investigated the role of FETUB in metabolic dysfunction-associated steatohepatitis (MASH) and the therapeutic efficacy of FETUB inhibition. In primary mouse hepatocytes, free fatty acid (FFA) stimulation upregulated FETUB transcription, expression, and secretion, which suppressed membrane AdipoR1 and triggered NLRP3/GSDMD-mediated pyroptosis, exacerbating steatosis. In high-fat diet (HFD)-induced MASH mice, hepatic FETUB expression increased concordantly with AdipoR1 downregulation. FETUB blockade ameliorated hepatic steatosis, inflammation, ballooning, and fibrosis by disrupting this pathway. These findings establish FETUB as a key regulator of NLRP3/GSDMD-driven pyroptosis in MASH and identify it as a promising therapeutic target.