Journal of nanobiotechnology · 2026
UBQLN1 Inhibition reduces MASH progression through downregulating SIKE/p38 MAPK pathway in hepatocyte.
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Chen Yifei, Yang Fuji, Zheng Guojun, Wang Yanjin, Liu Likang, Yan Yongmin
Аннотация
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.
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.