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Background <p><i>Hypericum perforatum</i> L. (Guan Ye Jin Si Tao, GYJST), commonly known as St. John’s wort, is a widely distributed medicinal plant across Europe and Asia. Preclinical studies have identified its therapeutic potential in both neurological and metabolic disorders. However, its impact on metabolic-associated fatty liver disease (MAFLD) remains unclear. This study comprehensively investigated the therapeutic effects of GYJST on MAFLD through both invivo and in vitro experiments. Utilizing a multi-omics approach, the research elucidated the regulatory mechanisms of GYJST on ferroptosis, focusing on oxidative stress, lipid metabolism, and inflammatory response modulation. The findings provide valuable insights into the potential therapeutic applications of GYJST in managing MAFLD.</p> Materials and methods <p>Liver assessments were systematically conducted to evaluate the therapeutic effects of GYJST on HFD-induced mice and PA-induced AML12 cells. Comprehensive histological analyses, including H&amp;E, Masson, Sirius Red, Oil Red O, and F4/80 staining, were performed to assess the impact of GYJST on liver pathology. To elucidate the underlying mechanisms of GYJST, a multi-omics approach was employed, integrating network pharmacology, transcriptomics, proteomics, and metabolomics. Additionally, RT-qPCR, western blotting, and immunofluorescence techniques were utilized to validate the effects of GYJST.</p> Results <p>GYJST effectively protects against liver injury by mitigating inflammation, oxidative stress, and lipid metabolism dysregulation. A total of 90 major compounds in GYJST were tentatively identified. Network pharmacology analysis revealed its multi-target, multi-pathway mechanisms of action. Integrative transcriptomic, metabolomic, and proteomic analyses consistently highlighted pathways associated with inflammatory responses, oxidative stress, and lipid metabolism. Mechanistically, GYJST suppresses systemic inflammation via the NF-κB/COX-2 signaling axis and alleviates oxidative stress and lipid accumulation through the Nrf2/PPARα/g pathway. Additionally, GYJST plays a crucial role in inhibiting ferroptosis, partly through Nrf2-mediated mechanisms.</p> Conclusion <p>GYJST exerts multi-target therapeutic effects against MAFLD by concurrently regulating ferroptosis, oxidative stress, lipid metabolism, and inflammation through interconnected mechanisms. These findings establish GYJST as a promising multi-target therapeutic candidate for MAFLD treatment.</p> Graphical Abstract <p></p>

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Hypericum perforatum L. extract alleviates metabolic-associated fatty liver disease through inflammation, lipid metabolism and ferroptosis modulation: a multi-omics perspective

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月3日

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  • Peng Huang,
  • Yunling Zhu,
  • Yidan Qin,
  • Jianguo Hu,
  • Jiancheng Wang,
  • Jian Qin

摘要

Background

Hypericum perforatum L. (Guan Ye Jin Si Tao, GYJST), commonly known as St. John’s wort, is a widely distributed medicinal plant across Europe and Asia. Preclinical studies have identified its therapeutic potential in both neurological and metabolic disorders. However, its impact on metabolic-associated fatty liver disease (MAFLD) remains unclear. This study comprehensively investigated the therapeutic effects of GYJST on MAFLD through both invivo and in vitro experiments. Utilizing a multi-omics approach, the research elucidated the regulatory mechanisms of GYJST on ferroptosis, focusing on oxidative stress, lipid metabolism, and inflammatory response modulation. The findings provide valuable insights into the potential therapeutic applications of GYJST in managing MAFLD.

Materials and methods

Liver assessments were systematically conducted to evaluate the therapeutic effects of GYJST on HFD-induced mice and PA-induced AML12 cells. Comprehensive histological analyses, including H&E, Masson, Sirius Red, Oil Red O, and F4/80 staining, were performed to assess the impact of GYJST on liver pathology. To elucidate the underlying mechanisms of GYJST, a multi-omics approach was employed, integrating network pharmacology, transcriptomics, proteomics, and metabolomics. Additionally, RT-qPCR, western blotting, and immunofluorescence techniques were utilized to validate the effects of GYJST.

Results

GYJST effectively protects against liver injury by mitigating inflammation, oxidative stress, and lipid metabolism dysregulation. A total of 90 major compounds in GYJST were tentatively identified. Network pharmacology analysis revealed its multi-target, multi-pathway mechanisms of action. Integrative transcriptomic, metabolomic, and proteomic analyses consistently highlighted pathways associated with inflammatory responses, oxidative stress, and lipid metabolism. Mechanistically, GYJST suppresses systemic inflammation via the NF-κB/COX-2 signaling axis and alleviates oxidative stress and lipid accumulation through the Nrf2/PPARα/g pathway. Additionally, GYJST plays a crucial role in inhibiting ferroptosis, partly through Nrf2-mediated mechanisms.

Conclusion

GYJST exerts multi-target therapeutic effects against MAFLD by concurrently regulating ferroptosis, oxidative stress, lipid metabolism, and inflammation through interconnected mechanisms. These findings establish GYJST as a promising multi-target therapeutic candidate for MAFLD treatment.

Graphical Abstract