Zhao Yanan, Lu Jing, Mao Ankang, Zhang Ranran, Guan Shuang
College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China.
Key Laboratory of Zoonosis, Ministry of Education College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, People's Republic of China.
J Agric Food Chem. 2021 Aug 25;69(33):9671-9683. doi: 10.1021/acs.jafc.1c03751. Epub 2021 Aug 13.
Binge alcohol consumption is a serious health concern. Ferroptosis is an iron-dependent lipid peroxidation mediated cell death. Activation of the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway has been shown to exert a protective effect by blunting the responses to ferroptosis inducers. The autophagy substrate p62 was demonstrated to modulate Nrf2 and contribute to the suppression of ferroptosis. Furthermore, autophagy inhibition resulted in the accumulation of p62, which is a specific substrate for this process. Therefore, we aimed to explore the protective effect of autophagy inhibition against alcohol-induced ferroptosis through activating the p62-Keap1-Nrf2 pathway. Our results demonstrated that alcohol induced ferroptosis, which could be significantly reduced by ferrostatin-1. Additionally, we found that autophagy inhibition could protect HepG2 cells against alcohol-induced ferroptosis by activating the p62-Keap1-Nrf2 pathway. Furthermore, inhibition of autophagy increased the expression of p62, which interacted with Keap1 to promote Nrf2 translocation into the nucleus and upregulation its target proteins ferritin heavy (FTH), ferroportin (FPN), and heme oxygenase-1 (HO-1). This study provides a theoretical basis for further elucidation of the relationship between autophagy and ferroptosis and lays a preliminary foundation for further research concerning dietary guidance in the prevention and treatment of diseases related to alcohol-induced ferroptosis.
暴饮酒精是一个严重的健康问题。铁死亡是一种铁依赖性脂质过氧化介导的细胞死亡。已有研究表明，激活 Kelch 样 ECH 相关蛋白 1（Keap1）-核因子红细胞 2 相关因子 2（Nrf2）通路可通过减弱对铁死亡诱导剂的反应发挥保护作用。自噬底物 p62 被证明可调节 Nrf2 并有助于抑制铁死亡。此外，自噬抑制导致 p62 积累，而 p62 是该过程的特异性底物。因此，我们旨在通过激活 p62-Keap1-Nrf2 通路来探索自噬抑制对酒精诱导的铁死亡的保护作用。我们的结果表明，酒精可诱导铁死亡，而铁抑素-1 可显著降低这种作用。此外，我们发现自噬抑制可通过激活 p62-Keap1-Nrf2 通路保护 HepG2 细胞免受酒精诱导的铁死亡。此外，自噬抑制增加了 p62 的表达，p62 与 Keap1 相互作用以促进 Nrf2 易位至细胞核并上调其靶蛋白铁蛋白重链（FTH）、铁转运蛋白（FPN）和血红素加氧酶-1（HO-1）。本研究为进一步阐明自噬与铁死亡之间的关系提供了理论依据，并为进一步研究酒精诱导的铁死亡相关疾病的饮食指导奠定了初步基础。
