nrf2激活的线粒体自噬和铁凋亡抑制协同介导橘皮素对肝缺血再灌注损伤的保护作用

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-07-01 DOI:10.1016/j.phymed.2025.157034

Deng Liu , Ruixin Zhang , Lixia Zha , Lei Yao , Youwen Han , Xiaolu Zhang , Yujia Chen , Mengting Zhan , Jian Du , Lijian Chen

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引用次数: 0

摘要

肝缺血再灌注（I/R）损伤是肝脏手术中常见的损伤，是术后肝衰竭和移植物功能障碍的重要因素。橘皮素（TAN）是一种存在于柑橘皮中的多甲氧基黄酮，具有显著的抗氧化和抗炎作用。尽管如此，其对肝脏I/R损伤的影响和机制仍不清楚。目的探讨TAN减轻肝I/R损伤的潜在作用及其机制。方法采用小鼠体内肝I/R模型和体外原代肝细胞氧糖剥夺/再灌注（OGD/R）模型，评价TAN对肝I/R损伤的保护作用。结果本研究阐明了TAN对原代肝细胞I/R和OGD/R损伤的保护机制。RNA-seq分析表明，TAN增强了线粒体相关的生物学功能，特别是线粒体自噬和铁下垂。我们的研究结果表明，TAN降低了线粒体膜电位（ΔΨm）损失和超氧化物水平。此外，TAN激活了肝细胞的线粒体自噬，降低了铁离子（Fe2+）和过氧化脂质（LPO）水平。值得注意的是，tan诱导的线粒体自噬减少了线粒体内Fe2+和LPO的积累，从而协同抑制铁下垂。机制上，分子对接和动态模拟研究表明，TAN与Nrf2/Keap1复合物具有较强的结合亲和力，促进Nrf2核易位，进而激活线粒体自噬，抑制肝细胞铁凋亡。与我们的结果一致，肝脏特异性Nrf2敲低消除了TAN的有丝分裂激活和抗铁下垂作用。结论TAN通过Nrf2通路和线粒体自噬激活协同抑制肝细胞铁凋亡，减轻肝缺血再灌注损伤，显示出治疗肝I/R损伤的新潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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

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

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.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.