Current medicinal chemistry · 2026
The dysregulation of tetrahydrobiopterin biosynthesis exacerbates the progression of chronic liver disease by modulating choline metabolism pathways and inflammatory responses.
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Jiang Jie, Hu Zongqiang, Li Li
Аннотация
BACKGROUND: Tetrahydrobiopterin (BH4) is a crucial cofactor in several biosynthetic pathways. Dysregulation of BH4 biosynthesis, particularly via sepiapterin reductase (SPR), has been implicated in chronic liver disease (CLD). This study investigates the role of SPR and BH4 in liver fibrosis progression.
METHODS: Clinical cirrhotic liver tissues were analyzed using liquid chromatography-mass spectrometry (LC-MS) to assess metabolite levels. Mouse models of liver injury (DDC, MCD, CCL4) were used to explore the impact of BH4 dysregulation. SPRi3, a selective SPR inhibitor, was administered to assess the effect of BH4 inhibition. Transcriptomic and metabolic changes were evaluated through RNA-seq and non-targeted metabolomics.
RESULTS: In cirrhotic liver tissues, BH4 levels were reduced, while sepiapterin was elevated, indicating dysregulated BH4 biosynthesis. In animal models, SPR expression was downregulated and correlated with worsening fibrosis. Inhibition of SPR using SPRi3 exacerbated liver injury, altered immune responses, and disrupted lipid metabolism. RNA-seq and metabolomics revealed changes in inflammation-related pathways, choline, and fatty acid metabolism. SPR-mediated dysregulation of BH4 biosynthesis contributes to liver injury and fibrosis progression in CLD.
CONCLUSIONS: Disruption of lipid and choline metabolism, alongside immune modulation, suggests that targeting the SPR/BH4 pathway may offer therapeutic potential for managing chronic liver diseases.
METHODS: Clinical cirrhotic liver tissues were analyzed using liquid chromatography-mass spectrometry (LC-MS) to assess metabolite levels. Mouse models of liver injury (DDC, MCD, CCL4) were used to explore the impact of BH4 dysregulation. SPRi3, a selective SPR inhibitor, was administered to assess the effect of BH4 inhibition. Transcriptomic and metabolic changes were evaluated through RNA-seq and non-targeted metabolomics.
RESULTS: In cirrhotic liver tissues, BH4 levels were reduced, while sepiapterin was elevated, indicating dysregulated BH4 biosynthesis. In animal models, SPR expression was downregulated and correlated with worsening fibrosis. Inhibition of SPR using SPRi3 exacerbated liver injury, altered immune responses, and disrupted lipid metabolism. RNA-seq and metabolomics revealed changes in inflammation-related pathways, choline, and fatty acid metabolism. SPR-mediated dysregulation of BH4 biosynthesis contributes to liver injury and fibrosis progression in CLD.
CONCLUSIONS: Disruption of lipid and choline metabolism, alongside immune modulation, suggests that targeting the SPR/BH4 pathway may offer therapeutic potential for managing chronic liver diseases.