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<p>Despite its strong regenerative capacity, liver aging paradoxically increases susceptibility to fibrosis and metabolic dysfunction-associated steatotic liver disease through dysregulated inflammation, senescence-associated secretory phenotypes, and immune-metabolic crosstalk. To systematically characterize these processes, we integrated longitudinal transcriptomics, single-cell RNA sequencing, and machine-learning approaches. We identified 252 aging-associated genes and developed an Aging Gene Score (AGS) to quantify senescence burden across hepatic cell populations. Single-cell analysis revealed macrophages as key drivers of fibrosis progression, with high-AGS myeloid subsets markedly expanded in cirrhotic livers. Using combined Boruta and LASSO algorithms, we established a five-gene biomarker panel (<i>EFEMP1</i>, <i>LUM</i>, <i>DKK3</i>, <i>GPRC5B</i>, <i>NCAM2</i>) that accurately predicts advanced fibrosis (AUC &gt; 0.77). Furthermore, a network pharmacology framework was applied to screen medicine-food homology (MFH) herbs, identifying <i>Fagopyrum dibotrys</i> (Jinqiaomai) and <i>Astragalus membranaceus</i> (Huangqi) as top candidates. Molecular docking demonstrated strong binding between the bioactive compound MOL000098 and the fibrosis-related target <i>COL3A1</i>. Functional assays showed that Jinqiaomai-containing serum alleviates oxidative stress, improves HepG2 cell viability, reduces ALT and AST levels, and suppresses macrophage lipid accumulation, accompanied by reduced expression of inflammatory and fibrosis-related markers. Collectively, our findings highlight macrophage-centered mechanisms linking liver aging and fibrosis and suggest MFH-derived compounds as promising anti-aging and anti-fibrotic dietary interventions.</p>

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Integrated transcriptomic analysis identifies liver aging-driven fibrosis signatures and reveals therapeutic strategies based on medicine-food homology

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月26日

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  • Yingqi Xu,
  • Maohao Li,
  • Lun Zhu,
  • Yawen Luo,
  • Wanlu Sheng,
  • Panlei Jia,
  • Rina Suo,
  • Lidao Bao

摘要

Despite its strong regenerative capacity, liver aging paradoxically increases susceptibility to fibrosis and metabolic dysfunction-associated steatotic liver disease through dysregulated inflammation, senescence-associated secretory phenotypes, and immune-metabolic crosstalk. To systematically characterize these processes, we integrated longitudinal transcriptomics, single-cell RNA sequencing, and machine-learning approaches. We identified 252 aging-associated genes and developed an Aging Gene Score (AGS) to quantify senescence burden across hepatic cell populations. Single-cell analysis revealed macrophages as key drivers of fibrosis progression, with high-AGS myeloid subsets markedly expanded in cirrhotic livers. Using combined Boruta and LASSO algorithms, we established a five-gene biomarker panel (EFEMP1, LUM, DKK3, GPRC5B, NCAM2) that accurately predicts advanced fibrosis (AUC > 0.77). Furthermore, a network pharmacology framework was applied to screen medicine-food homology (MFH) herbs, identifying Fagopyrum dibotrys (Jinqiaomai) and Astragalus membranaceus (Huangqi) as top candidates. Molecular docking demonstrated strong binding between the bioactive compound MOL000098 and the fibrosis-related target COL3A1. Functional assays showed that Jinqiaomai-containing serum alleviates oxidative stress, improves HepG2 cell viability, reduces ALT and AST levels, and suppresses macrophage lipid accumulation, accompanied by reduced expression of inflammatory and fibrosis-related markers. Collectively, our findings highlight macrophage-centered mechanisms linking liver aging and fibrosis and suggest MFH-derived compounds as promising anti-aging and anti-fibrotic dietary interventions.