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Background <p>Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly recognized as a major global contributor to cirrhosis and hepatocellular carcinoma (HCC). However, the key regulatory molecules governing lipid metabolism dysregulation, remains incompletely understood.</p> Methods <p>Clinical sample analyses, cellular models, animal models (HFHC and HFD/CCL4-induced MASH mice), and molecular biology techniques (transcriptomics, LC-MS/MS, etc.) were employed to elucidate the mechanistic of UBQLN1-mediated regulation of hepatocyte lipid accumulation in MASH and evaluates the therapeutic potential of UBQLN1-targeted interventions.</p> Results <p>The results indicated that UBQLN1 was significantly upregulated in both patients with MASH and in MASH mouse models, demonstrating a positive correlation with hepatic lipid deposition. Genetic knockdown of UBQLN1 markedly reduced hepatic steatosis, inflammatory cell infiltration, and fibrosis progression in MASH mice. Mechanistically, UBQLN1 initiated the p38 mitogen-activated protein kinase (p38 MAPK) pathway <i>via</i> the ubiquitin-mediated degradation of the suppressor of IKKε (SIKE) to promote lipid accumulation in hepatocytes. Furthermore, red blood cell-derived extracellular vesicles loaded with UBQLN1 siRNA (RBC-EVs@siUBQLN1) effectively mitigated lipid accumulation in hepatocytes and improved the progression of MASH <i>in vivo</i>.</p> Conclusions <p>These findings establish the UBQLN1-SIKE-p38 MAPK axis as a critical regulatory pathway in MASH pathogenesis and develop an RBC-EVs-targeted delivery system for MASH therapy.</p> Graphical abstract <p></p>

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UBQLN1 Inhibition reduces MASH progression through downregulating SIKE/p38 MAPK pathway in hepatocyte

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月11日

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  • Yifei Chen,
  • Fuji Yang,
  • Guojun Zheng,
  • Yanjin Wang,
  • Likang Liu,
  • Yongmin Yan

摘要

Background

Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly recognized as a major global contributor to cirrhosis and hepatocellular carcinoma (HCC). However, the key regulatory molecules governing lipid metabolism dysregulation, remains incompletely understood.

Methods

Clinical sample analyses, cellular models, animal models (HFHC and HFD/CCL4-induced MASH mice), and molecular biology techniques (transcriptomics, LC-MS/MS, etc.) were employed to elucidate the mechanistic of UBQLN1-mediated regulation of hepatocyte lipid accumulation in MASH and evaluates the therapeutic potential of UBQLN1-targeted interventions.

Results

The results indicated that UBQLN1 was significantly upregulated in both patients with MASH and in MASH mouse models, demonstrating a positive correlation with hepatic lipid deposition. Genetic knockdown of UBQLN1 markedly reduced hepatic steatosis, inflammatory cell infiltration, and fibrosis progression in MASH mice. Mechanistically, UBQLN1 initiated the p38 mitogen-activated protein kinase (p38 MAPK) pathway via the ubiquitin-mediated degradation of the suppressor of IKKε (SIKE) to promote lipid accumulation in hepatocytes. Furthermore, red blood cell-derived extracellular vesicles loaded with UBQLN1 siRNA (RBC-EVs@siUBQLN1) effectively mitigated lipid accumulation in hepatocytes and improved the progression of MASH in vivo.

Conclusions

These findings establish the UBQLN1-SIKE-p38 MAPK axis as a critical regulatory pathway in MASH pathogenesis and develop an RBC-EVs-targeted delivery system for MASH therapy.

Graphical abstract