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Background <p>This study aimed to verify the protective effect of Rosmarinic acid (RA) on sepsis-associated encephalopathy (SAE) and elucidate its downstream binding protein and mechanisms.</p> Materials and methods <p>A murine sepsis model was established. RA was administered 11d pre-CLP and 3d post-CLP to prevent and treat SAE. Then, behavioral, histopathological, and immunological assays were performed, along with RA safety evaluation. Metabolomic profiling identified differential metabolites in SAE mouse brain tissues. The targeting relationship between RA and ribonucleotide reductase subunit M2 (RRM2) was validated via DARTS, molecular docking, and Western blotting. An in vitro LPS-induced HT22 cell injury model was constructed; RA’s protective effects and regulatory role in purine metabolism via RRM2 were evaluated.</p> Results <p>RA alleviated cerebral edema, inflammation, oxidative stress, and M1 microglial activation, improved cognitive function, and protected against SAE-induced brain injury. Metabolomics revealed RA’s role in regulating purine metabolism, and its interaction with RRM2 was confirmed. In vitro, RA upregulated RRM2 expression, restored purine metabolic disorders, and mitigated LPS-induced HT22 cell damage.</p> Conclusions <p>RA was a promising therapeutic candidate for SAE. It interacted with RRM2 to regulate purine metabolism, inhibit inflammation and oxidative stress, and alleviate sepsis-induced brain damage.</p> Graphical Abstract <p></p>

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Rosmarinic acid regulated purine metabolism to alleviate septic-associated encephalopathy by regulating RRM2

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月21日

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  • Xiaokun Li,
  • Xiaoxia Chang,
  • Cong Jiang,
  • Yixian Wang,
  • Banghui Duan,
  • Wanyong Ma,
  • Jian Yu

摘要

Background

This study aimed to verify the protective effect of Rosmarinic acid (RA) on sepsis-associated encephalopathy (SAE) and elucidate its downstream binding protein and mechanisms.

Materials and methods

A murine sepsis model was established. RA was administered 11d pre-CLP and 3d post-CLP to prevent and treat SAE. Then, behavioral, histopathological, and immunological assays were performed, along with RA safety evaluation. Metabolomic profiling identified differential metabolites in SAE mouse brain tissues. The targeting relationship between RA and ribonucleotide reductase subunit M2 (RRM2) was validated via DARTS, molecular docking, and Western blotting. An in vitro LPS-induced HT22 cell injury model was constructed; RA’s protective effects and regulatory role in purine metabolism via RRM2 were evaluated.

Results

RA alleviated cerebral edema, inflammation, oxidative stress, and M1 microglial activation, improved cognitive function, and protected against SAE-induced brain injury. Metabolomics revealed RA’s role in regulating purine metabolism, and its interaction with RRM2 was confirmed. In vitro, RA upregulated RRM2 expression, restored purine metabolic disorders, and mitigated LPS-induced HT22 cell damage.

Conclusions

RA was a promising therapeutic candidate for SAE. It interacted with RRM2 to regulate purine metabolism, inhibit inflammation and oxidative stress, and alleviate sepsis-induced brain damage.

Graphical Abstract