Inhibition of the p62-Nrf2-GPX4 Pathway Confers Sensitivity to Butachlor-Induced Splenic Macrophage Ferroptosis,Journal of Agricultural and Food Chemistry

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Inhibition of the p62-Nrf2-GPX4 Pathway Confers Sensitivity to Butachlor-Induced Splenic Macrophage Ferroptosis
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2024-07-17 , DOI: 10.1021/acs.jafc.4c01086
Yi Zhao _{1,

2,

3} , Shang-Jia Yang ₁ , Yi-Feng Huang ₁ , Fu-Wei Jiang ₁ , Hong-Li Si ₁ , Ming-Shan Chen ₁ , Jia-Xin Wang ₁ , Shuo Liu ₁ , Yu-Jun Jiang ₄ , Jin-Long Li _{1,

2,

3}

Affiliation

Butachlor is widely used in agriculture around the world and therefore poses environmental and public health hazards due to persistent and poor biodegradability. Ferroptosis is a type of iron-mediated cell death controlled by glutathione (GSH) and GPX4 inhibition. P62 is an essential autophagy adaptor that regulates Keap1 to activate nuclear factor erythroid 2-related factor 2 (Nrf2), which effectively suppresses lipid peroxidation, thereby relieving ferroptosis. Here, we found that butachlor caused changes in splenic macrophage structure, especially impaired mitochondrial morphology with disordered structure, which is suggestive of the occurrence of ferroptosis. This was further confirmed by the detection of iron metabolism, the GSH system, and lipid peroxidation. Mechanistically, butachlor suppressed the protein level of p62 and promoted Keap1-mediated degradation of Nrf2, which results in decreased GPX4 expression and accelerated splenic macrophage ferroptosis. These findings suggest that targeting the p62-Nrf2-GPX4 signaling axis may be a promising strategy for treating inflammatory diseases.

中文翻译：

p62-Nrf2-GPX4 通路的抑制赋予对丁草胺诱导的脾巨噬细胞铁死亡的敏感性

丁草胺在世界各地的农业中广泛使用，由于其持久且生物降解性差，对环境和公共健康造成危害。铁死亡是一种由谷胱甘肽 (GSH) 和 GPX4 抑制控制的铁介导的细胞死亡。 P62是一种重要的自噬接头，可调节Keap1激活核因子红细胞2相关因子2（Nrf2），有效抑制脂质过氧化，从而缓解铁死亡。在这里，我们发现丁草胺引起脾巨噬细胞结构的变化，特别是线粒体形态受损，结构紊乱，提示铁死亡的发生。通过铁代谢、GSH系统和脂质过氧化的检测进一步证实了这一点。从机制上讲，丁草胺抑制 p62 的蛋白水平并促进 Keap1 介导的 Nrf2 降解，从而导致 GPX4 表达减少并加速脾巨噬细胞铁死亡。这些发现表明，针对 p62-Nrf2-GPX4 信号轴可能是治疗炎症性疾病的一种有前景的策略。

更新日期：2024-07-17

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