CircEXOC5 Aggravates Sepsis-Induced Acute Lung Injury by Promoting Ferroptosis Through the IGF2BP2/ATF3 Axis

作者：Wang, Wei^*; Xu, Rongli; He, Ping; Xiong, Yuqing; Zhao, Haomiao; Fu, Xuewei; Lin, Jie; Ye, Lijiao

来源：JOURNAL OF INFECTIOUS DISEASES, 2024, 229(2): 522-534.

DOI：10.1093/infdis/jiad337

• ATF3
• IGF2BP2
• acute lung injury
• circEXOC5
• ferroptosis
• sepsis

Background Patients with sepsis resulting in acute lung injury (ALI) usually have increased mortality. Ferroptosis is a vital regulator in sepsis-induced ALI. Exploring the association of ferroptosis and sepsis-induced ALI is crucial for the management of sepsis-induced ALI.Methods Whole blood was collected from sepsis patients. Mice were treated with cecal ligation and puncture (CLP) to model sepsis. Primary murine pulmonary microvascular endothelial cells were treated with lipopolysaccharide as a cell model. Ferroptosis was evaluated by analyzing levels of iron, malonaldehyde, glutathione, nonheme iron, ferroportin, ferritin, and GPX4. Hematoxylin and eosin and Masson's trichrome staining were applied to examine lung injury and collagen deposition. Cell apoptosis was analyzed by caspase-3 activity and TUNEL assays. Gene regulatory relationship was verified using RNA pull-down and immunoprecipitation assays.Results CircEXOC5 was highly expressed in sepsis patients and CLP-treated mice, in which knockdown alleviated CLP-induced pulmonary inflammation and injury, and ferroptosis. CircEXOC5 recruited IGF2BP2 to degrade ATF3 mRNA. The demethylase ALKBH5 was responsible for circEXOC5 upregulation through demethylation. CircEXOC5 silencing significantly improved sepsis-induced ALI and survival rate of mice by downregulating ATF3.Conclusions ALKBH5-mediated upregulation of circEXOC5 exacerbates sepsis-induced ALI by facilitating ferroptosis through IGF2BP2 recruitment to degrade ATF3 mRNA. @@@ Sepsis primarily causes acute lung injury (ALI). Here, we demonstrate that circEXOC5 promotes ferroptosis through the IGF2BP2/ATF3 axis to aggravate sepsis-induced ALI. Our findings provide novel mechanistic insights into sepsis-induced ALI and suggest potential therapeutic targets.

• 单位
  1; 南方医科大学; 海南医学院