期刊
CELL DEATH & DISEASE
卷 13, 期 6, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-022-04971-x
关键词
-
类别
资金
- National Natural Science Foundation of China [81703205]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Foundation from Chongqing Yuzhong District Science and Technology Bureau [201930]
- Natural Science Foundation of Chongqing Science and Technology Bureau [cstc2020jcyj-msxm3187, cstc2020jcyj-msxm3430]
This study identified STAT6 as a critical regulator of epithelial ferroptosis during acute lung injury (ALI). STAT6 negatively regulates ferroptosis by competitively binding with CBP, inhibiting P53 acetylation and restoring SLC7A11 expression. Overexpression of STAT6 attenuated ALI-induced lung injury. STAT6 may be a potential therapeutic target for the treatment of ALI.
Compelling evidences have revealed the emerging role of ferroptosis in the pathophysiological process of acute lung injury (ALI), but its modulation is not clear. Here, we identified that STAT6 acted as a critical regulator of epithelium ferroptosis during ALI. Firstly, STAT6 expression and activity were increased in the ALI mice models caused by crystalline silica (CS), LPS and X-ray exposure. Followed by confirming the contribution of ferroptosis in the above ALI with ferrostatin-1 and deferoxamine intervention, bioinformatic analyses revealed that STAT6 expression was negatively correlated with ferroptosis. Consistently, lung epithelium-specific depletion of STAT6 in mice or STAT6 knockdown in cultured epithelial cells exacerbated ferroptosis in the above ALI. While overexpression of STAT6 in lung epithelial cells attenuated the ferroptosis. Mechanistically, SLC7A11 is a typical ferroptosis-related gene and negatively regulated by P53. CREB-binding protein (CBP) is a critical acetyltransferase of P53 acetylation, showing valuable regulation on targets' transcription. Herein, we found that STAT6 negatively regulates ferroptosis through competitively binding with CBP, which inhibits P53 acetylation and transcriptionally restores SLC7A11 expression. Finally, pulmonary-specific STAT6 overexpression decreased the ferroptosis and attenuated CS and LPS induced lung injury. Our findings revealed that STAT6 is a pivotal regulator of ferroptosis, which may be a potential therapeutic target for the treatment of acute lung injury.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据