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Background <p>Glutathione (GSH) metabolism plays a crucial role in the development and progression of non-alcoholic fatty liver disease (NAFLD), yet its molecular mechanism remains unclear.</p> Methods <p>Bulk transcriptome and single-cell data from the Gene Expression Omnibus (GEO) database were analyzed using single-cell RNA sequencing (scRNA-seq) and five algorithms for Glutathione metabolism-related genes (GMRGs) scores to identify key cell types and biomarkers. Core candidate biomarker was validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting in palmitic acid (PA)-induced HepG2 cells.</p> Results <p>Cholangiocytes showed the highest GMRG-related transcriptional activity among the annotated cell populations. Through screening, 4 potential biomarkers (CSTA, DDAH2, OAZ2, TYMP) were found, with DDAH2 as the core due to its high expression and strong correlation with GMRGs. Enrichment analysis suggested that DDAH2 expression was associated with energy metabolism and protein homeostasis pathways. DDAH2-high cholangiocytes showed stronger computationally inferred interactions with B cells and endothelial cells, mainly involving the “MIF-(CD74 + CXCR4)” and “APP-CD74” pathways, and were enriched in early pseudotime states. In vitro, DDAH2 expression was significantly up-regulated in NAFLD, providing preliminary support for the expression trend.</p> Conclusion <p>This study identified cholangiocytes as the annotated cell population with the strongest GSH metabolism-related transcriptional signature in the analyzed NAFLD scRNA-seq dataset and highlighted four related biomarkers, with DDAH2 prioritized as the core candidate biomarker.</p>

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Identification of glutathione metabolism-related biomarkers in non-alcoholic fatty liver disease based on single-cell and bulk RNA sequencing

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Yinan Zhao,
  • Guoying Yu,
  • Lu Zhao

摘要

Background

Glutathione (GSH) metabolism plays a crucial role in the development and progression of non-alcoholic fatty liver disease (NAFLD), yet its molecular mechanism remains unclear.

Methods

Bulk transcriptome and single-cell data from the Gene Expression Omnibus (GEO) database were analyzed using single-cell RNA sequencing (scRNA-seq) and five algorithms for Glutathione metabolism-related genes (GMRGs) scores to identify key cell types and biomarkers. Core candidate biomarker was validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting in palmitic acid (PA)-induced HepG2 cells.

Results

Cholangiocytes showed the highest GMRG-related transcriptional activity among the annotated cell populations. Through screening, 4 potential biomarkers (CSTA, DDAH2, OAZ2, TYMP) were found, with DDAH2 as the core due to its high expression and strong correlation with GMRGs. Enrichment analysis suggested that DDAH2 expression was associated with energy metabolism and protein homeostasis pathways. DDAH2-high cholangiocytes showed stronger computationally inferred interactions with B cells and endothelial cells, mainly involving the “MIF-(CD74 + CXCR4)” and “APP-CD74” pathways, and were enriched in early pseudotime states. In vitro, DDAH2 expression was significantly up-regulated in NAFLD, providing preliminary support for the expression trend.

Conclusion

This study identified cholangiocytes as the annotated cell population with the strongest GSH metabolism-related transcriptional signature in the analyzed NAFLD scRNA-seq dataset and highlighted four related biomarkers, with DDAH2 prioritized as the core candidate biomarker.