2. Academic Validation
  3. Fetuin B drives metabolism-associated steatohepatitis by promoting hepatocyte pyroptosis via NLRP3/GSDMD pathway

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

  • Exp Cell Res. 2026 Mar 1;456(1):114886. doi: 10.1016/j.yexcr.2026.114886.
Shi Chen 1,  Yue Wang 2,  Jingwen Gao 3,  Jiaxi Lin 4,  Lu Liu 4,  Shiqi Zhu 4,  Lihe Liu 4,  Chunfang Xu 4,  Xiaolin Liu 4,  Manhui Zhu 5,  Jinzhou Zhu 6
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, Tumor Hospital Affiliated to Nantong University, Nantong Tumor Hospital, Nantong, China.
  • 2 Department of Hepatology, The Fifth People's Hospital of Suzhou, Suzhou, Jiangsu, China.
  • 3 Department of Gastroenterology, Suzhou Municipal Hospital, Suzhou, Jiangsu, China.
  • 4 Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Suzhou Clinical Center of Digestive Diseases, Suzhou, Jiangsu, China.
  • 5 Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: [email protected].
  • 6 Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Suzhou Clinical Center of Digestive Diseases, Suzhou, Jiangsu, China. Electronic address: [email protected].
PMID: 41506566 DOI: 10.1016/j.yexcr.2026.114886
Abstract

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.

Keywords

And PYD domains-containing protein 3 (NLRP3); Fetuin B (FETUB); LRR; Metabolism-associated steatohepatitis (MASH); NACHT; pyroptosis.

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