2. Academic Validation
  3. 7,8-Dihydroxyflavone protects acetaminophen induced liver injury through activating PI3K/Akt/NRF2/GPX4 mediated ferroptosis suppression

7,8-Dihydroxyflavone protects acetaminophen induced liver injury through activating PI3K/Akt/NRF2/GPX4 mediated ferroptosis suppression

  • Free Radic Biol Med. 2025 Oct 30:242:275-287. doi: 10.1016/j.freeradbiomed.2025.10.297.
Xintong Pei 1,  Rong Mu 2,  Siyi Liu 3,  Lu Xiong 4,  Xianli Wang 5,  Qi Yao 6,  Hongbo Qi 7,  Hui Li 8
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing, 401147, China; NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing, 401147, China; Chongqing Municipal Health Commission Key Laboratory of Perinatal Medicine, Chongqing, 401147, China. Electronic address: peixintong1993@163.com.
  • 2 Zunyi Medical University, Zunyi, 563006, China; Chongqing Municipal Health Commission Key Laboratory of Perinatal Medicine, Chongqing, 401147, China. Electronic address: 565910885@qq.com.
  • 3 Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing, 401147, China. Electronic address: liusiyi1233@163.com.
  • 4 Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing, 401147, China. Electronic address: 919214601@qq.com.
  • 5 Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing, 401147, China. Electronic address: 1369241087@qq.com.
  • 6 Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing, 401147, China; NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing, 401147, China; Chongqing Municipal Health Commission Key Laboratory of Perinatal Medicine, Chongqing, 401147, China. Electronic address: yaoqi_wh@163.com.
  • 7 Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing, 401147, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Chongqing Municipal Health Commission Key Laboratory of Perinatal Medicine, Chongqing, 401147, China; Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, 400016, China. Electronic address: qihongbo@cqmu.edu.cn.
  • 8 Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing, 401147, China; NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing, 401147, China; Chongqing Municipal Health Commission Key Laboratory of Perinatal Medicine, Chongqing, 401147, China. Electronic address: lihui_wh1983@163.com.
PMID: 41173313 DOI: 10.1016/j.freeradbiomed.2025.10.297
Abstract

Acetaminophen (APAP)-induced liver injury remains a leading cause of acute liver failure, with limited therapeutic options beyond the narrow therapeutic window of N-acetylcysteine. Emerging evidence highlights Ferroptosis as a critical mediator of APAP hepatotoxicity. Here, we investigated the hepatoprotective effects of 7,8-dihydroxyflavone (7,8-DHF), a natural flavonoid with antioxidative properties, against APAP-induced liver injury and explored its underlying mechanisms. In a murine model of APAP overdose, 7,8-DHF administration significantly attenuated liver damage, as evidenced by reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, preserved histological integrity, and suppressed oxidative stress, evidenced by a rescue of APAP-induced 4-hydroxynonenal and malondialdehyde level. Transcriptomic analyses revealed that 7,8-DHF reversed APAP-induced dysregulation of lipid metabolism and Reactive Oxygen Species (ROS) pathways. Mechanistically, 7,8-DHF promoted nuclear translocation of NRF2, upregulated GPX4 and SLC7A11 expression, and inhibited ferroptosis-associated factors (PTGS2, ACSL4). Pharmacological inhibition of PI3K/Akt or NRF2 abrogated 7,8-DHF-mediated Ferroptosis suppression and hepatoprotection in vitro and in vivo. Collectively, our findings identify 7,8-DHF as a promising therapeutic agent for APAP-induced liver injury through modulation of the PI3K/Akt/NRF2/GPX4 axis, offering a novel strategy to target Ferroptosis in drug-induced liver injury.

Keywords

7,8-Dihydroxyflavone; Acetaminophen; Ferroptosis; Liver injury; NRF2.

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