FOXO3 drives glycolytic reprogramming-associated hepatocyte stress and TNF⍺ production in liver cirrhosis
Description
Background: Liver cirrhosis (LC) is characterized by progressive hepatocellular injury and inflammatory activation. However, the metabolic regulators that drive hepatocyte injury in the cirrhotic microenvironment remain poorly defined. Methods: Integrative analyses combining bulk transcriptomics with single-nucleus RNA sequencing were performed to identify LC–glycolysis genes. Pseudotime analysis was performed to investigate dynamic changes in cell populations during disease progression. Multiple enrichment analyses and AUCell were conducted to characterize gene functions. Immunohistochemistry, immunofluorescence, and western blotting were used for experimental validation in cell models, a bile duct ligation (BDL) mouse model, and patients with liver cirrhosis. Results: Forkhead box O3 (FOXO3) was identified as an LC–glycolysis gene. It was predominantly upregulated in hepatocytes, particularly within a stress-associated subpopulation with enhanced glycolysis. Pseudotime analysis revealed a progressive increase in FOXO3 expression during disease progression. Enrichment analyses revealed activation of the hypoxia response, unfolded protein response, apoptosis, and mitophagy, characterizing a specific stressed hepatocyte subpopulation that links metabolic reprogramming and inflammatory activation. TNFα signalling was also elevated in stressed hepatocytes. Experimental validation in HepG2 cells, BDL mouse models, and human cirrhotic tissues confirmed increased FOXO3 and TNFα expression, along with increased expression levels of apoptosis and fibrosis markers. Conclusion: FOXO3 appears to drive LC progression by modulating glycolysis-associated stress responses via mitophagy and activating TNFα signalling in hepatocytes.
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Institutions
- Second Affiliated Hospital of Harbin Medical UniversityHeilongjiang, Harbin