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Background <p><i>Ganoderma lucidum</i> (<i>G. lucidum</i>) is a medicinal mushroom known for its hepatoprotective effects against various liver diseases.</p> Objective <p>Addressing the variable quality of <i>G. lucidum</i> samples and the lack of efficacy-linked quality control criteria, an integrated strategy combining chemical analysis and biological validation was conducted to identify the Q-markers directly responsible for its anti-hepatic fibrosis (HF) activity and to preliminarily elucidate their action mechanism.</p> Methods <p>49 batches of <i>G. lucidum</i> samples were collected from 15 geographical origins across 7 provinces in China. Initially, UPLC fingerprinting integrated with chemometric analysis evaluated the quality and identified differential chemical components. The common compounds were further characterized by UPLC-Orbitrap-HRMS. Subsequently, the potential targets and binding affinity were predicted by network pharmacology and molecular docking. Finally, the anti-HF activity and underlying mechanism of the core Q-marker were verified in a TGF-β1-induced HSC-T6 model using CCK-8, flow cytometry, immunofluorescence, and Western blotting.</p> Results <p>The UPLC chemical fingerprint of <i>G. lucidum</i> was successfully established, 49 common components were identified based on UPLC-Orbitrap-HRMS analysis, mostly were triterpenoids. Through chemometric analysis, 19 key differential markers were subsequently screened. Then, by integrating network pharmacology predictions with chemometric screening results, 7 triterpenoids were ultimately determined as potential Q-markers for the anti-HF activity of <i>G. lucidum</i>. Ganoderic acid J (GAJ) demonstrated robust binding specificity to pivotal targets within the PI3K/AKT signaling pathway through molecular docking. 5, 10, and 20&#xa0;µg/mL at 24&#xa0;h were confirmed as low, medium, and high doses of GAJ by CCK-8, respectively. Ultimately, HF was relieved by suppressing the PI3K/AKT pathway, promoting apoptosis in activated HSCs and normalizing the MMP1/MMP2 equilibrium.</p> Conclusion <p>The anti-HF effects of <i>G. lucidum</i> were mediated through multi-target synergistic actions, chiefly by suppressing the PI3K/AKT pathway and modulating extracellular matrix metabolism. The hepatoprotective mechanism of <i>G. lucidum</i> was elucidated at the molecular level, and a Q-marker-based theoretical framework was established for quality control of traditional medicines and innovative drug development.</p> Graphical abstract <p></p>

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An integrated strategy for screening Q-markers and elucidating anti-fibrotic mechanisms of Ganoderma lucidum

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月28日

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  • Yuanyuan Sun,
  • Shujie Yuan,
  • Wenhui Luo,
  • Jie Wang,
  • Renting Cao,
  • Meng Su,
  • Chijing Zuo,
  • Can Peng,
  • Jing Zhang

摘要

Background

Ganoderma lucidum (G. lucidum) is a medicinal mushroom known for its hepatoprotective effects against various liver diseases.

Objective

Addressing the variable quality of G. lucidum samples and the lack of efficacy-linked quality control criteria, an integrated strategy combining chemical analysis and biological validation was conducted to identify the Q-markers directly responsible for its anti-hepatic fibrosis (HF) activity and to preliminarily elucidate their action mechanism.

Methods

49 batches of G. lucidum samples were collected from 15 geographical origins across 7 provinces in China. Initially, UPLC fingerprinting integrated with chemometric analysis evaluated the quality and identified differential chemical components. The common compounds were further characterized by UPLC-Orbitrap-HRMS. Subsequently, the potential targets and binding affinity were predicted by network pharmacology and molecular docking. Finally, the anti-HF activity and underlying mechanism of the core Q-marker were verified in a TGF-β1-induced HSC-T6 model using CCK-8, flow cytometry, immunofluorescence, and Western blotting.

Results

The UPLC chemical fingerprint of G. lucidum was successfully established, 49 common components were identified based on UPLC-Orbitrap-HRMS analysis, mostly were triterpenoids. Through chemometric analysis, 19 key differential markers were subsequently screened. Then, by integrating network pharmacology predictions with chemometric screening results, 7 triterpenoids were ultimately determined as potential Q-markers for the anti-HF activity of G. lucidum. Ganoderic acid J (GAJ) demonstrated robust binding specificity to pivotal targets within the PI3K/AKT signaling pathway through molecular docking. 5, 10, and 20 µg/mL at 24 h were confirmed as low, medium, and high doses of GAJ by CCK-8, respectively. Ultimately, HF was relieved by suppressing the PI3K/AKT pathway, promoting apoptosis in activated HSCs and normalizing the MMP1/MMP2 equilibrium.

Conclusion

The anti-HF effects of G. lucidum were mediated through multi-target synergistic actions, chiefly by suppressing the PI3K/AKT pathway and modulating extracellular matrix metabolism. The hepatoprotective mechanism of G. lucidum was elucidated at the molecular level, and a Q-marker-based theoretical framework was established for quality control of traditional medicines and innovative drug development.

Graphical abstract