• Jianfei Niu, Wei Guo, Aiyangzi Lu, Guanxiong Han, Guanqun Wang, Bihui Peng, and Jiping Zhao.
• Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing, China.
• Medicine (Baltimore). 2023 Oct 13; 102 (41): e35002e35002.

AbstractFerroptosis-inducing agents (FIAs) induced lipid-peroxidation-independent ferroptosis in eosinophils, thus ameliorating airway inflammation in asthmatic mice. Differences in ferroptosis-related genes (FerrGs) between eosinophils and cells in which FIAs induce canonical ferroptosis are supposed to contribute to this noncanonical ferroptosis but remain unclear. This study aims to explore these differences. This study used gastric cancer cells (GCCs) in stomach adenocarcinoma as the representative of cells in which FIAs induce canonical ferroptosis. FerrGs in Ferroptosis Database V2 respectively intersected with differentially expressed genes (DEGs) of eosinophils (E-MTAB-4660 dataset) and GCCs (GEPIA2 Stomach adenocarcinoma dataset) to obtain original ferroptosis DEGs (FerrDEGs). Then, they were subjected to Venn analysis to identify FerrDEGs shared by them and FerrDEGs exclusively expressed in eosinophils or GCCs. Identified genes were subjected to functional enrichment analysis, protein-protein interactions analysis, Hub genes analysis, and construction of the LncRNA-mediated ceRNA network. Sixty-six original FerrDEGs in eosinophils and 110 original FerrDEGs in GCCs were obtained. Venn analysis identified that eosinophils and GCCs shared 19 FerrDEGs that presented opposite expression directions and were involved in the ferroptosis pathway. Four upregulated and 20 downregulated FerrDEGs were exclusively expressed in eosinophils and GCCs, respectively. The former were enriched only in glycerolipid metabolism, while the latter were not enriched in pathways. Forty downregulated and 68 upregulated FerrDEGs were solely expressed in eosinophils and GCCs, respectively. The former was associated with the FoxO signaling pathway; the latter was related to glutathione metabolism and they were all implicated in autophagy. PPI analysis shows that the top 10 Hub genes of 66 original FerrDEGs and 44 exclusive FerrDEGs in eosinophils shared 9 genes (STAT3, NFE2L2, MAPK8, PTEN, MAPK3, TLR4, SIRT1, BECN1, and PTGS2) and they were also involved in the FoxO signaling pathway and autophagy pathway. Among them, PTEN is involved in forming a ceRNA network containing 3 LncRNAs, 3 miRNAs and 3 mRNAs. In contrast to FerrGs in cells in which FIAs induce canonical ferroptosis, the FerrGs in eosinophils differ in expression and in the regulation of ferroptosis, FoxO signaling pathway, and autophagy. It lays the groundwork for targeted induction of eosinophils lipid-peroxidation-independent ferroptosis in asthma.Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.

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