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<p>Excessive acetaminophen (APAP) intake is a major cause of acute liver injury, primarily through its conversion to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which induces oxidative stress and ferroptosis, a form of iron-dependent, lipid peroxidation-mediated cell death. This study investigated the hepatoprotective effects of vitamin K1(Vit K1) and its role in modulating ferroptosis via the Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2) / heme oxygenase-1 (HO-1) antioxidant pathway. Male mice were pretreated with Vit K1 (1, 2, or 3 mg/kg) prior to APAP injection (200 mg/kg). Liver damage was assessed by serum biomarkers Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and albumin, oxidative stress markers including reduced glutathione (GSH), malondialdehyde (MDA) and Nitric Oxide (NO), and ferroptosis indicators glutathione peroxidase 4 (GPX4), hepatic iron, acyl-CoA synthetase Long-chain family member 4 (ACSL4). APAP significantly increased ALT, AST, MDA, NO, and iron, while reducing albumin, GSH, and GPX4 levels, indicating oxidative injury and ferroptosis. Vit K1 pretreatment ameliorated these effects dose-dependently by restoring antioxidant balance, suppressing ACSL4 and Keap1 expression, and upregulating Nrf2 and HO-1. These results suggest that Vit K1 may protect against APAP-induced hepatotoxicity by inhibiting ferroptosis and activating antioxidant responses through the Keap1-Nrf2/HO-1 pathway, supporting its potential as a therapeutic candidate for drug-induced liver injury.&#xa0;</p>

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Vitamin K1 attenuates acetaminophen-induced ferroptotic hepatic damage in mice via targeting keap1/Nrf2/HO-1 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月7日

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  • Shimaa A. Abass,
  • Ahmed A. Mohamed,
  • Ahmed H. Abd El-Slam,
  • Abdalrahman M. Yousef,
  • Mohammed Karim Ayoub,
  • Basma Salah,
  • Walied Abdo,
  • Mona Mohammed Abdel Hamid

摘要

Excessive acetaminophen (APAP) intake is a major cause of acute liver injury, primarily through its conversion to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which induces oxidative stress and ferroptosis, a form of iron-dependent, lipid peroxidation-mediated cell death. This study investigated the hepatoprotective effects of vitamin K1(Vit K1) and its role in modulating ferroptosis via the Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2) / heme oxygenase-1 (HO-1) antioxidant pathway. Male mice were pretreated with Vit K1 (1, 2, or 3 mg/kg) prior to APAP injection (200 mg/kg). Liver damage was assessed by serum biomarkers Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and albumin, oxidative stress markers including reduced glutathione (GSH), malondialdehyde (MDA) and Nitric Oxide (NO), and ferroptosis indicators glutathione peroxidase 4 (GPX4), hepatic iron, acyl-CoA synthetase Long-chain family member 4 (ACSL4). APAP significantly increased ALT, AST, MDA, NO, and iron, while reducing albumin, GSH, and GPX4 levels, indicating oxidative injury and ferroptosis. Vit K1 pretreatment ameliorated these effects dose-dependently by restoring antioxidant balance, suppressing ACSL4 and Keap1 expression, and upregulating Nrf2 and HO-1. These results suggest that Vit K1 may protect against APAP-induced hepatotoxicity by inhibiting ferroptosis and activating antioxidant responses through the Keap1-Nrf2/HO-1 pathway, supporting its potential as a therapeutic candidate for drug-induced liver injury.