Sakuranetin Prevents Acetaminophen-Induced Liver Injury via Nrf2-Induced Inhibition of Hepatocyte Ferroptosis
Zhida Long,* Xiao Yu,* Shijia Li, Nuo Cheng, Chenglong Huo, Xuewen Zhang, Shuai Wang Department of Hepatobiliary Surgery, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People’s Republic of China*These authors contributed equally to this workCorresponden...
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Dove Medical Press
2025-01-01
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| author | Long Z Yu X Li S Cheng N Huo C Zhang X Wang S |
| author_facet | Long Z Yu X Li S Cheng N Huo C Zhang X Wang S |
| author_sort | Long Z |
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| description | Zhida Long,* Xiao Yu,* Shijia Li, Nuo Cheng, Chenglong Huo, Xuewen Zhang, Shuai Wang Department of Hepatobiliary Surgery, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuai Wang, Department of Hepatobiliary Surgery, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People’s Republic of China, Email l10095@yangtzeu.edu.cnIntroduction: Oxidative stress is an important cause of acetaminophen (APAP)-induced liver injury (AILI). Sakuranetin (Sak) is an antitoxin from the cherry flavonoid plant with good antioxidant effects. However, whether sakuranetine has a protective effect on APAP-induced liver injury is not clear.Methods: Mouse and HepG2 cell models of APAP injury were used to investigate the effect of sakuranetin on AILI and its mechanism. Serum transaminase levels, histological changes, inflammatory mediators, oxidative stress, ferroptosis-related markers and Nrf2 signaling pathway proteins were analyzed.Results: Sakuranetin significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as inflammatory factor; increased HepG2 activity and decreased cell death; inhibited ROS production, increased glutathione (GSH) content, expression of Glutathione Peroxidase 4 (GPX4) and Solute Carrier Family 7 Member 11 (SLC7A11), and decreased malondialdehyde and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) expression in mice and HepG2 cells after APAP treatment. Further analysis showed that sakuranetin induced the activation of the NFE2 Like BZIP Transcription Factor 2 (Nrf2) signaling pathway in liver tissue and HepG2 cells and promoted the nuclear translocation of Nrf2. Moreover, the hepatoprotective effect of sakuranetin and its inhibitory effect on ferroptosis were significantly attenuated by the Nrf2 inhibitor ML385.Conclusion: Sakuranetin alleviates AILI by activating the Nrf2 signaling pathway and inhibiting ferroptosis, and sakuranetin may be a potential therapeutic agent for the treatment of AILI.Keywords: sakuranetin, AILI, ferroptosis, oxidation, Nrf2 |
| format | Article |
| id | doaj-art-51acb0ffe7564d79b90a6e4f703325bc |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-51acb0ffe7564d79b90a6e4f703325bc2025-01-12T16:52:42ZengDove Medical PressDrug Design, Development and Therapy1177-88812025-01-01Volume 1915917199149Sakuranetin Prevents Acetaminophen-Induced Liver Injury via Nrf2-Induced Inhibition of Hepatocyte FerroptosisLong ZYu XLi SCheng NHuo CZhang XWang SZhida Long,* Xiao Yu,* Shijia Li, Nuo Cheng, Chenglong Huo, Xuewen Zhang, Shuai Wang Department of Hepatobiliary Surgery, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuai Wang, Department of Hepatobiliary Surgery, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People’s Republic of China, Email l10095@yangtzeu.edu.cnIntroduction: Oxidative stress is an important cause of acetaminophen (APAP)-induced liver injury (AILI). Sakuranetin (Sak) is an antitoxin from the cherry flavonoid plant with good antioxidant effects. However, whether sakuranetine has a protective effect on APAP-induced liver injury is not clear.Methods: Mouse and HepG2 cell models of APAP injury were used to investigate the effect of sakuranetin on AILI and its mechanism. Serum transaminase levels, histological changes, inflammatory mediators, oxidative stress, ferroptosis-related markers and Nrf2 signaling pathway proteins were analyzed.Results: Sakuranetin significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as inflammatory factor; increased HepG2 activity and decreased cell death; inhibited ROS production, increased glutathione (GSH) content, expression of Glutathione Peroxidase 4 (GPX4) and Solute Carrier Family 7 Member 11 (SLC7A11), and decreased malondialdehyde and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) expression in mice and HepG2 cells after APAP treatment. Further analysis showed that sakuranetin induced the activation of the NFE2 Like BZIP Transcription Factor 2 (Nrf2) signaling pathway in liver tissue and HepG2 cells and promoted the nuclear translocation of Nrf2. Moreover, the hepatoprotective effect of sakuranetin and its inhibitory effect on ferroptosis were significantly attenuated by the Nrf2 inhibitor ML385.Conclusion: Sakuranetin alleviates AILI by activating the Nrf2 signaling pathway and inhibiting ferroptosis, and sakuranetin may be a potential therapeutic agent for the treatment of AILI.Keywords: sakuranetin, AILI, ferroptosis, oxidation, Nrf2https://www.dovepress.com/sakuranetin-prevents-acetaminophen-induced-liver-injury-via-nrf2-induc-peer-reviewed-fulltext-article-DDDTsakuranetinailiferroptosisoxidationnrf2 |
| spellingShingle | Long Z Yu X Li S Cheng N Huo C Zhang X Wang S Sakuranetin Prevents Acetaminophen-Induced Liver Injury via Nrf2-Induced Inhibition of Hepatocyte Ferroptosis Drug Design, Development and Therapy sakuranetin aili ferroptosis oxidation nrf2 |
| title | Sakuranetin Prevents Acetaminophen-Induced Liver Injury via Nrf2-Induced Inhibition of Hepatocyte Ferroptosis |
| title_full | Sakuranetin Prevents Acetaminophen-Induced Liver Injury via Nrf2-Induced Inhibition of Hepatocyte Ferroptosis |
| title_fullStr | Sakuranetin Prevents Acetaminophen-Induced Liver Injury via Nrf2-Induced Inhibition of Hepatocyte Ferroptosis |
| title_full_unstemmed | Sakuranetin Prevents Acetaminophen-Induced Liver Injury via Nrf2-Induced Inhibition of Hepatocyte Ferroptosis |
| title_short | Sakuranetin Prevents Acetaminophen-Induced Liver Injury via Nrf2-Induced Inhibition of Hepatocyte Ferroptosis |
| title_sort | sakuranetin prevents acetaminophen induced liver injury via nrf2 induced inhibition of hepatocyte ferroptosis |
| topic | sakuranetin aili ferroptosis oxidation nrf2 |
| url | https://www.dovepress.com/sakuranetin-prevents-acetaminophen-induced-liver-injury-via-nrf2-induc-peer-reviewed-fulltext-article-DDDT |
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