Rosmarinic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Suppressing Ferroptosis and Oxidative Stress Through Nrf2/HO-1 Activation in Mice
Liver injury caused by the irrational use of acetaminophen (APAP) represents a significant challenge in the field of public health. In clinical treatment, apart from N—acetylcysteine (NAC), the only approved antidote, there are extremely limited effective intervention measures for APAP-induced hepat...
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2025-07-01
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| author | Liqin Wu Li Lv Yifei Xiang Dandan Yi Qiuling Liang Min Ji Zhaoyou Deng Lanqian Qin Lingyi Ren Zhengmin Liang Jiakang He |
| author_facet | Liqin Wu Li Lv Yifei Xiang Dandan Yi Qiuling Liang Min Ji Zhaoyou Deng Lanqian Qin Lingyi Ren Zhengmin Liang Jiakang He |
| author_sort | Liqin Wu |
| collection | DOAJ |
| description | Liver injury caused by the irrational use of acetaminophen (APAP) represents a significant challenge in the field of public health. In clinical treatment, apart from N—acetylcysteine (NAC), the only approved antidote, there are extremely limited effective intervention measures for APAP-induced hepatotoxicity. Therefore, exploring novel liver-protecting drugs and elucidating their mechanisms of action is of great scientific significance and clinical value. Rosmarinic acid (RA), as a natural polyphenolic compound, has been proven to have significant antioxidant activity. Previous studies have shown that it has a protective effect against drug-induced liver injury. Nevertheless, the precise protective mechanism of RA in APAP-induced acute liver injury (AILI) has not been fully defined. This study was based on an AILI mouse model to systematically explore the liver-protecting effect of RA and its underlying molecular mechanisms. The research results showed that pretreatment with RA could notably mitigate liver pathological injury. It could decrease the activities of ALT and AST in the serum, suppress the liver inflammatory reaction, and reverse the decline in the levels of CAT, T-AOC, SOD, and GSH caused by APAP. Meanwhile, RA could enhance antioxidant defense capabilities by activating the Keap1/Nrf2/HO-1 signaling pathway, regulate the <i>xCT</i>/GPX4 axis to inhibit lipid peroxidation, and thus block the process of ferroptosis. In conclusion, this study confirmed that RA exerts a protective effect against AILI by regulating the Keap1/Nrf2/HO-1 axis to enhance antioxidant capacity and inhibit ferroptosis through the <i>xCT</i>/GPX4 pathway. Our research provides a theoretical basis for RA as a potential therapeutic agent for APAP-induced liver injury. |
| format | Article |
| id | doaj-art-b209828af6a249df8eed7498a0f6029f |
| institution | DOAJ |
| issn | 1660-3397 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj-art-b209828af6a249df8eed7498a0f6029f2025-08-20T03:08:12ZengMDPI AGMarine Drugs1660-33972025-07-0123728710.3390/md23070287Rosmarinic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Suppressing Ferroptosis and Oxidative Stress Through Nrf2/HO-1 Activation in MiceLiqin Wu0Li Lv1Yifei Xiang2Dandan Yi3Qiuling Liang4Min Ji5Zhaoyou Deng6Lanqian Qin7Lingyi Ren8Zhengmin Liang9Jiakang He10Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi Zhuang Autonomous Region Engineering Research Center of Veterinary Biologics, Guangxi University, Nanning 530004, ChinaGuangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi Zhuang Autonomous Region Engineering Research Center of Veterinary Biologics, Guangxi University, Nanning 530004, ChinaGuangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi Zhuang Autonomous Region Engineering Research Center of Veterinary Biologics, Guangxi University, Nanning 530004, ChinaGuangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi Zhuang Autonomous Region Engineering Research Center of Veterinary Biologics, Guangxi University, Nanning 530004, ChinaGuangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi Zhuang Autonomous Region Engineering Research Center of Veterinary Biologics, Guangxi University, Nanning 530004, ChinaGuangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi Zhuang Autonomous Region Engineering Research Center of Veterinary Biologics, Guangxi University, Nanning 530004, ChinaGuangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi Zhuang Autonomous Region Engineering Research Center of Veterinary Biologics, Guangxi University, Nanning 530004, ChinaGuangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi Zhuang Autonomous Region Engineering Research Center of Veterinary Biologics, Guangxi University, Nanning 530004, ChinaGuangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi Zhuang Autonomous Region Engineering Research Center of Veterinary Biologics, Guangxi University, Nanning 530004, ChinaGuangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi Zhuang Autonomous Region Engineering Research Center of Veterinary Biologics, Guangxi University, Nanning 530004, ChinaGuangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi Zhuang Autonomous Region Engineering Research Center of Veterinary Biologics, Guangxi University, Nanning 530004, ChinaLiver injury caused by the irrational use of acetaminophen (APAP) represents a significant challenge in the field of public health. In clinical treatment, apart from N—acetylcysteine (NAC), the only approved antidote, there are extremely limited effective intervention measures for APAP-induced hepatotoxicity. Therefore, exploring novel liver-protecting drugs and elucidating their mechanisms of action is of great scientific significance and clinical value. Rosmarinic acid (RA), as a natural polyphenolic compound, has been proven to have significant antioxidant activity. Previous studies have shown that it has a protective effect against drug-induced liver injury. Nevertheless, the precise protective mechanism of RA in APAP-induced acute liver injury (AILI) has not been fully defined. This study was based on an AILI mouse model to systematically explore the liver-protecting effect of RA and its underlying molecular mechanisms. The research results showed that pretreatment with RA could notably mitigate liver pathological injury. It could decrease the activities of ALT and AST in the serum, suppress the liver inflammatory reaction, and reverse the decline in the levels of CAT, T-AOC, SOD, and GSH caused by APAP. Meanwhile, RA could enhance antioxidant defense capabilities by activating the Keap1/Nrf2/HO-1 signaling pathway, regulate the <i>xCT</i>/GPX4 axis to inhibit lipid peroxidation, and thus block the process of ferroptosis. In conclusion, this study confirmed that RA exerts a protective effect against AILI by regulating the Keap1/Nrf2/HO-1 axis to enhance antioxidant capacity and inhibit ferroptosis through the <i>xCT</i>/GPX4 pathway. Our research provides a theoretical basis for RA as a potential therapeutic agent for APAP-induced liver injury.https://www.mdpi.com/1660-3397/23/7/287rosmarinic acidacetaminophenliver injuryoxidative damageferroptosis |
| spellingShingle | Liqin Wu Li Lv Yifei Xiang Dandan Yi Qiuling Liang Min Ji Zhaoyou Deng Lanqian Qin Lingyi Ren Zhengmin Liang Jiakang He Rosmarinic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Suppressing Ferroptosis and Oxidative Stress Through Nrf2/HO-1 Activation in Mice Marine Drugs rosmarinic acid acetaminophen liver injury oxidative damage ferroptosis |
| title | Rosmarinic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Suppressing Ferroptosis and Oxidative Stress Through Nrf2/HO-1 Activation in Mice |
| title_full | Rosmarinic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Suppressing Ferroptosis and Oxidative Stress Through Nrf2/HO-1 Activation in Mice |
| title_fullStr | Rosmarinic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Suppressing Ferroptosis and Oxidative Stress Through Nrf2/HO-1 Activation in Mice |
| title_full_unstemmed | Rosmarinic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Suppressing Ferroptosis and Oxidative Stress Through Nrf2/HO-1 Activation in Mice |
| title_short | Rosmarinic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Suppressing Ferroptosis and Oxidative Stress Through Nrf2/HO-1 Activation in Mice |
| title_sort | rosmarinic acid protects against acetaminophen induced hepatotoxicity by suppressing ferroptosis and oxidative stress through nrf2 ho 1 activation in mice |
| topic | rosmarinic acid acetaminophen liver injury oxidative damage ferroptosis |
| url | https://www.mdpi.com/1660-3397/23/7/287 |
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