Nrf2-activated mitophagy and ferroptosis suppression synergistically mediate tangeretin's protection against hepatic ischemia-reperfusion injury

  • Phytomedicine. 2025 Sep:145:157034. doi: 10.1016/j.phymed.2025.157034.
Deng Liu  1 ,  Ruixin Zhang  1 ,  Lixia Zha  1 ,  Lei Yao  2 ,  Youwen Han  1 ,  Xiaolu Zhang  1 ,  Yujia Chen  1 ,  Mengting Zhan  1 ,  Jian Du  3 ,  Lijian Chen  4
Affiliations
  • 1. Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China; Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, PR China.
  • 2. Department of Biochemistry and Molecular Biology, Infectious Disease Research Center, School of Basic Medical Sciences, Anhui Medical University, Hefei, PR China.
  • 3. Department of Biochemistry and Molecular Biology, Infectious Disease Research Center, School of Basic Medical Sciences, Anhui Medical University, Hefei, PR China. Electronic address: [email protected].
  • 4. Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China; Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, PR China. Electronic address: [email protected].
PMID: 40617054 DOI: 10.1016/j.phymed.2025.157034
Abstract

Background: Liver ischemia-reperfusion (I/R) injury frequently arises during liver surgery and significantly contributes to postoperative liver failure and graft dysfunction. Tangeretin (TAN), a polymethoxy flavone present in citrus peel, has demonstrated notable antioxidant and anti-inflammatory effects. Despite this, its effects and mechanisms underlying liver I/R injury remain unclear.

Purpose: This study aimed to investigate the potential effects and underlying mechanisms of TAN in mitigating liver I/R injury.

Methods: We utilized in vivo liver I/R models in mice, as well as in vitro oxygen-glucose deprivation/reperfusion (OGD/R) models in primary hepatocytes, and to assess the role of TAN against liver I/R injury.

Results: This study elucidated the protective mechanisms of TAN against hepatic I/R and OGD/R injury in primary hepatocytes. RNA-seq analysis indicated that TAN enhanced mitochondria-related biological functions, specifically Mitophagy and Ferroptosis. Our findings showed that TAN reduced mitochondrial membrane potential (ΔΨm) loss and superoxide levels. Furthermore, TAN activated Mitophagy and lowered ferrous ion (Fe2+) and lipid peroxide (LPO) levels in hepatocytes. Remarkably, TAN-induced Mitophagy reduced the accumulation of Fe2+ and LPO within the mitochondria, thereby synergistically inhibiting Ferroptosis. Mechanistically, molecular docking and dynamic simulation studies indicated a strong binding affinity between TAN and the Nrf2/Keap1 complex, facilitating Nrf2 nuclear translocation, which subsequently activated Mitophagy and suppressed hepatocytes Ferroptosis. Consistent with our results, liver-specific Nrf2 knockdown abolished the mitophagy-activating and anti-ferroptosis effects of TAN.

Conclusions: By synergistically inhibiting hepatocytes Ferroptosis through the Nrf2 pathway and Mitophagy activation, TAN alleviates liver ischemia-reperfusion injury, highlighting the novel therapeutic potential in liver I/R injury.

Keywords
Ferroptosis; Liver ischemia-reperfusion injury; Mitophagy; Nrf2; Tangeretin.
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