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<p>Severe liver injury can result from an overdose of acetaminophen (APAP). Rhein (RA) has shown a strong capability of combating inflammation and oxidative stress. Our study aimed to investigate the potential of RA in protecting the liver from APAP-induced damage and elucidate the mechanism of action. C57BL/6 mice received a pretreatment with intragastric 100&#xa0;mg/kg/day RA, followed by 400&#xa0;mg/kg/day APAP intraperitoneally. Liver injury was assessed via histopathology (hematoxylin and eosin (HE)-staining), serum biochemical indicators. AML-12 cells were treated with APAP or RA, and oxidative stress and apoptosis markers were evaluated. The underlying molecular mechanisms were examined by Western blotting (WB) and quantitative Real-time polymerase chain reaction (qPCR). RA treatment significantly alleviated hepatic injury caused by APAP in rodent model, reduced oxidative stress and apoptosis, and exerted a cytoprotective effect on AML-12 cells. RA increased intracellular glutathione (GSH) content and the GSH/GSSG (Glutathione disulfide) ratio, thereby enhancing the GSH redox cycle through the Nrf2 (Nuclear factor erythroid 2–related factor 2)-GCL (glutamate cysteine ligase)/GSR (glutathione-disulfide reductase) pathway. In addition, RA inhibited the expression of CYP2E1 and CYP1A2, the enzymes converting APAP into the NAPQI (N-acetyl-p-benzoquinone imine), thus effectively mitigating APAP-induced DILI (Drug Induced Liver Injury). We identified that RA prevents APAP-induced DILI liver injury by upregulating Nrf2 and inhibiting APAP-activating enzymes.</p>

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Rhein Prevents APAP-induced drug-induced Liver Injury by Upregulating Nrf2 and Inhibiting APAP-activating Enzymes

  • 期刊论文

  • 发表日期：

    2026年1月18日

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  • Mingda Liu,
  • Jin Dai,
  • Liangding Dou,
  • Zifeng Deng,
  • Junxian Liu,
  • Xin Hou,
  • Jinwen Zhang,
  • YongChao Huang,
  • Zhi Huang,
  • Dai Wang,
  • Dongbei Guo,
  • Ran An,
  • Youliang Yao,
  • Yongxing Zhang

摘要

Severe liver injury can result from an overdose of acetaminophen (APAP). Rhein (RA) has shown a strong capability of combating inflammation and oxidative stress. Our study aimed to investigate the potential of RA in protecting the liver from APAP-induced damage and elucidate the mechanism of action. C57BL/6 mice received a pretreatment with intragastric 100 mg/kg/day RA, followed by 400 mg/kg/day APAP intraperitoneally. Liver injury was assessed via histopathology (hematoxylin and eosin (HE)-staining), serum biochemical indicators. AML-12 cells were treated with APAP or RA, and oxidative stress and apoptosis markers were evaluated. The underlying molecular mechanisms were examined by Western blotting (WB) and quantitative Real-time polymerase chain reaction (qPCR). RA treatment significantly alleviated hepatic injury caused by APAP in rodent model, reduced oxidative stress and apoptosis, and exerted a cytoprotective effect on AML-12 cells. RA increased intracellular glutathione (GSH) content and the GSH/GSSG (Glutathione disulfide) ratio, thereby enhancing the GSH redox cycle through the Nrf2 (Nuclear factor erythroid 2–related factor 2)-GCL (glutamate cysteine ligase)/GSR (glutathione-disulfide reductase) pathway. In addition, RA inhibited the expression of CYP2E1 and CYP1A2, the enzymes converting APAP into the NAPQI (N-acetyl-p-benzoquinone imine), thus effectively mitigating APAP-induced DILI (Drug Induced Liver Injury). We identified that RA prevents APAP-induced DILI liver injury by upregulating Nrf2 and inhibiting APAP-activating enzymes.