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Background <p>Research has suggested that the modulation of the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway plays a vital role in the development of liver diseases. However, the specific molecular mechanisms that govern metabolic-associated steatotic liver disease (MASLD) have not been fully elucidated. This study aimed to explore and confirm the biomarkers related to the cGAS–STING pathway in the context of MASLD.</p> Methods <p>Using the data from public databases, key module genes associated with the cGAS–STING pathway were intersected with differentially expressed genes between the MASLD and control groups to identify candidate genes. Then, the biomarkers were determined using protein–protein interaction networks, machine learning, receiver operating characteristic curves, and expression validation. Subsequently, a nomogram was established and evaluated. The regulatory mechanisms of the biomarkers were further explored using enrichment analysis, immune infiltration, regulatory network analysis, drug prediction. Finally, RT-qPCR was performed to validate biomarker expression in animal samples.</p> Results <p>Based on the screening results, ENPP1 and MET were identified as biomarkers. The established nomogram demonstrated that the biomarkers were good predictors of MASLD occurrence. Enrichment analysis revealed that the Notch signaling pathway and adherens junction were co-enriched by the two biomarkers. Both biomarkers showed a significant correlation with different types of immune cells, including M1 macrophages. Notably, four miRNAs were found to co-target ENPP1 and MET, among which miR-300 and miR-301b exhibited significantly upregulated expression in the MASLD model group. Seven drugs, such as crizotinib and semaxanib, were predicted to target MET, whereas ribavirin was predicted to target ENPP1. Immunohistochemistry, RT-qPCR, and western blotting demonstrated reduced ENPP1 and MET expression in MASLD samples.</p> Conclusion <p>ENPP1 and MET were identified as biomarkers associated with the cGAS–STING pathway in MASLD, offering new insights into therapeutic and preventive strategies targeting this condition.</p>

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Investigation of ENPP1 and MET as biomarkers of the cGAS–STING pathway in metabolic-associated steatotic liver disease: an analysis based on public databases

  • 期刊论文

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  • 发表日期：

    2026年7月6日

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  • Wenyu Gao,
  • Tao Jiang,
  • Canmei Zhong,
  • Fenglin Chen

摘要

Background

Research has suggested that the modulation of the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway plays a vital role in the development of liver diseases. However, the specific molecular mechanisms that govern metabolic-associated steatotic liver disease (MASLD) have not been fully elucidated. This study aimed to explore and confirm the biomarkers related to the cGAS–STING pathway in the context of MASLD.

Methods

Using the data from public databases, key module genes associated with the cGAS–STING pathway were intersected with differentially expressed genes between the MASLD and control groups to identify candidate genes. Then, the biomarkers were determined using protein–protein interaction networks, machine learning, receiver operating characteristic curves, and expression validation. Subsequently, a nomogram was established and evaluated. The regulatory mechanisms of the biomarkers were further explored using enrichment analysis, immune infiltration, regulatory network analysis, drug prediction. Finally, RT-qPCR was performed to validate biomarker expression in animal samples.

Results

Based on the screening results, ENPP1 and MET were identified as biomarkers. The established nomogram demonstrated that the biomarkers were good predictors of MASLD occurrence. Enrichment analysis revealed that the Notch signaling pathway and adherens junction were co-enriched by the two biomarkers. Both biomarkers showed a significant correlation with different types of immune cells, including M1 macrophages. Notably, four miRNAs were found to co-target ENPP1 and MET, among which miR-300 and miR-301b exhibited significantly upregulated expression in the MASLD model group. Seven drugs, such as crizotinib and semaxanib, were predicted to target MET, whereas ribavirin was predicted to target ENPP1. Immunohistochemistry, RT-qPCR, and western blotting demonstrated reduced ENPP1 and MET expression in MASLD samples.

Conclusion

ENPP1 and MET were identified as biomarkers associated with the cGAS–STING pathway in MASLD, offering new insights into therapeutic and preventive strategies targeting this condition.