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Reduced ZMPSTE24 expression leads to prelamin accumulation and development of steatosis in MASLD patients

Joseph D Schinderle1,2, Anqi Wu1,2, Irina M Bochkis3,4

  • 1Department of Pathology, University of Pittsburgh School of Medicine, BST South, Room S446 200 Lothrop Street, Pittsburgh, PA, 15261, USA.

Scientific Reports
|November 26, 2025
PubMed

Insights

Metabolic-associated steatotic liver disease (MASLD) is linked to nuclear lamina defects caused by reduced ZMPSTE24 enzyme activity. Restoring ZMPSTE24 may offer a new therapeutic strategy for MASLD.

Area of Science:

  • Hepatology and Molecular Biology
  • Nuclear Structure and Gene Regulation

Background:

  • Metabolic-associated steatotic liver disease (MASLD) is increasingly prevalent, particularly in individuals with type 2 diabetes mellitus (T2D) and obesity.
  • Previous work linked nuclear lamina alterations to MASLD pathogenesis, involving chromatin changes and lipid metabolism.
  • Mutations in nuclear lamina genes, such as LMNA, are associated with fatty liver conditions.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying nuclear envelope changes in MASLD patients.
  • To identify the specific protein responsible for these nuclear lamina alterations.
  • To explore the role of p53 and microRNAs in MASLD development.

Main Methods:

  • Analysis of nuclear envelope components in MASLD patients.
  • Investigating the function of zinc metalloproteinase Ste24 (ZMPSTE24) in prelamin processing.
  • Utilizing Zmpste24 mutant mouse models to study hepatic steatosis and gene expression.
  • Functional analysis of p53 and FOXA2 in MASLD-related gene regulation.
  • Examining the role of mir-141-3p in ZMPSTE24 expression.

Main Results:

  • Downregulation of ZMPSTE24 was identified as the cause of nuclear envelope changes in MASLD patients, leading to prelamin accumulation.
  • Zmpste24 knockout mice exhibited hepatic steatosis and upregulation of p53 target genes.
  • p53 was confirmed as a regulator of differentially expressed genes in MASLD patients, consistent with Zmpste24 knockout findings.
  • ZMPSTE24 expression is repressed by mir-141-3p in male MASLD patients.
  • These findings establish a direct link between ZMPSTE24 downregulation, nuclear lamina defects, and MASLD development.

Conclusions:

  • MASLD can be considered a type of laminopathy due to ZMPSTE24 downregulation-induced nuclear lamina dysfunction.
  • Targeting ZMPSTE24 expression and restoring nuclear lamina integrity represent potential therapeutic strategies for MASLD.
  • Further research into the role of p53 and mir-141-3p could provide additional insights into MASLD pathogenesis.
Keywords:
MASLDNuclear laminaPrelaminSteatosisZMPSTE24

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