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

Patients with sepsis accompanying with acute lung injury (ALI) usually suffer from 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.Whole blood was collected from sepsis patients. Mice were treated with caecal ligation and puncture (CLP) for modeling sepsis. Primary murine pulmonary microvascular endothelial cells (PMVECs) were treated with LPS as a cell model. Ferroptosis was evaluated by analyzing levels of iron, MDA, GSH, non-heme 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.CircEXOC5 was highly expressed in sepsis patients and CLP-treated mice, of 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 through ATF3.ALKBH5-mediated upregulation of circEXOC5 exacerbates sepsis-induced ALI via facilitating ferroptosis through IGF2BP2 recruitment for degrading ATF3 mRNA.