ObjectivesAbdominal aortic aneurysm (AAA) is a cardiovascular disease with high mortality and pathogenesis closely related to various cell death types, e.g., autophagy, apoptosis and pyroptosis. However, the association between AAA and ferroptosis is unknown.MethodsGSE57691 and GSE98278 dataset were obtained from the Gene Expression Omnibus database, and a ferroptosis-related gene (FRG) set was downloaded from the FerrDb database. These data were normalized, and ferroptosis-related differentially expressed genes (FDEGs, AAA vs. normal samples) were identified using the limma package in R. FRGs expression was analyzed by Gene Set Expression Analysis (GSEA), and FDEGs were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) pathway enrichment analyses using the clusterProfiler package in R and ClueGO in Cytoscape. Protein–protein interaction networks were assembled using Cytoscape, and crucial FDEGs were identified using CytoHubba. Critical FDEG transcription factors (TFs) were predicted with iRegulon. FDEGs were verified in GSE98278 set, and key FDEGs in AAA (compared with normal samples) and ruptured AAA (RAAA; compared with AAA samples) were identified. Ferroptosis-related immune cell infiltration and correlations with key genes were analyzed by CIBERSORT. Key FEDGs were reverified in Ang II-induced AAA models of ApoE–/– and CD57B/6J mice by immunofluorescence assay.ResultsIn AAA and normal samples, 40 FDEGs were identified, and the expression of suppressive FRGs was significantly downregulated with GSEA. For FDEGs, the GO terms were response to oxidative stress and cellular response to external stimulus, and the KEGG pathways were the TNF and NOD-like receptor signaling pathways. IL6, ALB, CAV1, PTGS2, NOX4, PRDX6, GPX4, HSPA5, HSPB1, and NCF2 were the most enriched genes in the crucial gene cluster. CEBPG, NFAT5, SOX10, GTF2IRD1, STAT1, and RELA were potential TFs affecting these crucial genes. Ferroptosis-related immune cells involved in AAA formation were CD8+ T, naive CD4+ T, and regulatory T cells (Tregs); M0 and M2 macrophages; and eosinophils. Tregs were also involved in RAAA. GPX4, SLC2A1, and PEBP1 expression was downregulated in both the RAAA and AAA samples. GPX4 and PEBP1 were more important in AAA because they influenced ferroptosis-related immune cell infiltration, and SLC2A1 was more important in RAAA.ConclusionsThis is the first study to show that ferroptosis is crucial to AAA/RAAA formation. The TNF and NOD-like signaling pathways and ferroptosis-related immune cell infiltration play key roles in AAA/RAAA. GPX4 is a key ferroptosis-related gene in AAA. Ferroptosis and related genes might be promising targets in the treatment of AAA/RAAA.

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Background: B cells and autoantibodies play an important role in the pathogenesis of abdominal aortic aneurysm (AAA). IgG glycosylations are highly valued as potential disease biomarkers and therapeutic targets. Methods: Lectin microarray was applied to analyze the expression profile of serum IgG glycosylation in 75 patients with AAA, 68 autoimmune disease controls, and 100 healthy controls. Lectin blots were performed to validate the differences. The clinical relevance of lectins binding from the microarray results was explored in AAA patients. Results: Significantly lower binding level of SBA (preferred GalNAc) was observed for the AAA group compared with DCs (p < 0.001) and HCs (p = 0.049). A significantly lower binding level of ConA (preferred mannose) was observed in patients with aneurysm diameter >5 cm. Significantly higher binding of CSA (preferred GalNAc) was present for dyslipidemia patients, whereas a lower binding level of AAL (preferred fucose) was observed for hypertensive patients. Patients with diabetes had lower binding levels of IRA (preferred GalNAc) and HPA (preferred GalNAc) compared with those not with DM. PTL-L (R = 0.36, p = 0.0015, preferred GalNAc) was positively associated with aneurysm diameters, whereas DSL (R = 0.28, p = 0.014, preferred (GlcNAc)2-4) was positively associated with patients’ age. Symptomatic patients had a lower binding level of ConA (p = 0.032), and patients with coronary heart disease had higher binding levels of STL (p = 0.0029, preferred GlcNAc). Patients with ILT bound less with black bean crude (p = 0.04, preferred GalNAc). Conclusions: AAA was associated with a decreased IgG binding level of SBA (recognizing glycan GalNAc). Symptomatic patients with aneurysm <5 cm had a higher binding level of ConA (preferred mannose). Coronary heart disease and elder age were associated with increased IgG bisecting GlcNAc. IgG O-glycosylation (GalNAc) may play an important role in AAA pathogenesis and progression.