金丝桃苷通过调节线粒体钙超载介导的过度自噬，减轻玉米赤霉烯酮诱导的肝损伤

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-19 DOI:10.1016/j.phymed.2025.156880

Tianyu Han , Lulu Wang , Yan jiang , Shanshan Fei , Yiding Liu , Zhijun Liu , Tong Wang , Baiwen Guan , Yu Yang , Guangliang Shi

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引用次数: 0

摘要

玉米赤霉烯酮（ZEA）是发霉植物中最常见的真菌毒素之一，可引起肝脏铁下垂。金丝桃苷（Hyp）主要来源于贯叶连翘（Hypericum perforatum），具有保护肝脏、神经和心脏的作用。目的研究Hyp对zea诱导的肝损伤的保护作用，并阐明其机制。方法采用H&；E染色及透射电镜观察，以ALT和AST水平为指标，观察Hyp对zea所致肝损伤的保护作用。通过测定线粒体自噬和凋亡相关指标来确定Hyp对凋亡的保护作用。采用CETSA和siRNA转染检测Hyp对MCU蛋白的靶向性。结果Hyp可减轻zea诱导的肝细胞铁下垂和过度的有丝分裂，通过siRNA敲低Hyp或FUNDC1可降低AML12细胞的铁下垂。此外，Hyp减弱了ZEA暴露诱导的Gpx4与FUNDC1的相互作用，逆转了谷胱甘肽过氧化物酶4在线粒体中的募集和降解。Hyp被发现靶向MCU蛋白，以减轻线粒体Ca2+超载和线粒体自噬引起的上调ZEA暴露。MCU敲低可逆转zea诱导的线粒体自噬。Hyp还能逆转zea诱导的线粒体过度分裂和线粒体功能损伤。结论本研究表明，Hyp可通过抑制线粒体Ca2+超载的线粒体自噬来减轻ZEA诱导的铁下垂。我们的研究结果为Hyp作为减轻铁中毒相关肝损伤的有效治疗提供了证据。

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Hyperoside alleviates zearalenone-induced liver injury by regulating mitochondrial calcium overload mediated excessive autophagy

Background

Zearalenone (ZEA), one of the most common mycotoxins in moldy plants, can cause ferroptosis in the liver. Hyperoside (Hyp) is mainly derived from Hypericum perforatum and exerts hepatoprotective, neuroprotective, and cardioprotective effects. It is not known whether Hyp alleviates ZEA-induced ferroptosis-related damage

Aim

The protective effect of Hyp on ZEA-induced liver injury was studied and its underlying mechanisms were elucidated.

Methods

The protective effect of Hyp on ZEA-induced liver injury was determined based on ALT and AST levels and by using H&E staining and transmission electron microscopy. The protective effect of Hyp in attenuating ferroptosis was determined by measuring mitophagy- and ferroptosis-related indices. CETSA and siRNA transfection were used to determine the targeting of Hyp to MCU protein.

Results

Hyp attenuated ZEA-induced ferroptosis and excessive mitophagy in hepatocytes, and use of Hyp or FUNDC1 knockdown by siRNA decreased ferroptosis in AML12 cells. Furthermore, Hyp attenuated ZEA exposure–induced Gpx4 interaction with FUNDC1 and reversed the recruitment and degradation of glutathione peroxidase 4 to mitochondria. Hyp was found to target MCU protein to attenuate mitochondrial Ca²⁺ overload and mitophagy induced by upregulated ZEA exposure. MCU knockdown reversed ZEA-induced mitophagy. Hyp also reversed ZEA-induced excessive mitochondrial fission and impairment in mitochondrial function.

Conclusion

Our study demonstrated that Hyp could alleviate ZEA induced ferroptosis by targeting MCU to inhibit mitochondrial Ca²⁺overloaded mitophagy.Our findings provide evidence for Hyp as an effective treatment in alleviating ferroptosis-related liver 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.