PM2.5 inhibits system Xc- activity to induce ferroptosis by activating the AMPK-Beclin1 pathway in acute lung injury.
PM2.5 inhibits system Xc- activity to induce ferroptosis by activating the AMPK-Beclin1 pathway in acute lung injury.
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DOI：
10.2139/ssrn.4113130
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发表时间：
2022-09
影响因子：
6.8
通讯作者：
Kun Yan;Tian-Zhong Hou;Laiyu Zhu;X. Ci;Liping Peng
中科院分区：
文献类型：
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作者：
Kun Yan;Tian-Zhong Hou;Laiyu Zhu;X. Ci;Liping Peng
城市空气中的细颗粒物（PM2.5）是一种全球性污染源，与多种涉及多种类型的调节细胞死亡（RCD）的呼吸系统疾病密切相关。然而，铁下垂（一种新型的RCD）在pm2.5诱导的急性肺损伤（ALI）中的作用尚未阐明。在此，我们定义了铁下垂在pm2.5诱导的ALI模型中的作用和机制。首先，我们证明了ALI模型中脂质过氧化和铁积累显著增强，并伴随着amp激活的蛋白激酶(AMPK)- beclin1信号通路的激活和Xc-系统关键亚基SLC7A11的抑制。然而，这些异常被铁下垂抑制剂部分逆转。我们进一步发现Beclin1敲低或过表达分别改善或加剧了pm2.5诱导的铁下垂。在机制上，我们证实Beclin1通过直接结合SLC7A11来阻断System Xc-活性以触发铁死亡。最后，通过AAV-shRNA敲低Beclin1或抑制Beclin1上游激活因子AMPK，可改善pm2.5诱导的铁下垂和ALI。综上所述，我们的研究结果揭示了铁下沉在PM2.5诱导的ALI中起着新的作用，并阐明了AMPK-Beclin1通路和Xc-系统的具体机制，这可能为PM2.5对呼吸系统疾病的毒理学效应提供新的见解。
Urban airborne fine particulate matter (PM2.5) is a global pollution source that has been strongly related to multiple respiratory diseases involving various types of regulated cell death (RCD). However, the role of ferroptosis, a novel form of RCD, in PM2.5-induced acute lung injury (ALI), has not been elucidated. Herein, we define the role and mechanism of ferroptosis in a PM2.5-induced ALI model. First, we demonstrated that lipid peroxidation and iron accumulation were significantly enhanced in ALI models and were accompanied by activation of the AMP-activated protein kinase (AMPK)-Beclin1 signaling pathway and inhibition of the key subunit SLC7A11 of System Xc-. However, these abnormalities were partially reversed by ferroptosis inhibitors. We further revealed that Beclin1 knockdown or overexpression ameliorated or exacerbated PM2.5-induced ferroptosis, respectively. Mechanistically, we verified that Beclin1 blocks System Xc- activity to trigger ferroptosis by directly binding to SLC7A11. Finally, knockdown of Beclin1 by AAV-shRNA or inhibition of AMPK, an upstream activator of Beclin1, ameliorated PM2.5-induced ferroptosis and ALI. Taken together, our results revealed that ferroptosis plays a novel role in PM2.5-induced ALI and elucidated the specific mechanism involving the AMPK-Beclin1 pathway and System Xc-, which may provide new insight into the toxicological effects of PM2.5 on respiratory problems.