Identification of ferroptosis-related therapeutic targets and causal risk factors in aortic dissection via multi-omics integration.

The role of ferroptosis in the pathogenesis of aortic dissection (AD) has not been fully clarified. Data from the gene expression omnibus database were analyzed to identify differentially expressed ferroptosis-related genes (FRGs) in AD. Key FRGs were selected using Least Absolute Shrinkage and Selection Operator regression and validated with receiver operating characteristic analysis. Single-cell RNA sequencing was applied to assess expression patterns in specific cell types. Mendelian randomization was further performed using genome-wide association study summary statistics for 211 gut microbial taxa and 1400 serum metabolites to explore causal associations with AD. A total of 14 differentially expressed FRGs were identified. Among them, 7 genes (CHAC1, CDO1, HILPDA, GSK3B, DPEP1, BRD4, and NUPR1) were recognized as key candidates. GSK3B and BRD4 were significantly downregulated in endothelial cells, while DPEP1 showed reduced expression in fibroblasts. Immune cell analysis indicated an increase in neutrophils and a decrease in NK and dendritic cells in AD tissues. Regulatory network prediction identified 194 microRNAs, 218 long noncoding RNAs, and 61 potential therapeutic drugs targeting the key FRGs. Mendelian randomization analysis suggested causal associations between AD risk and 8 gut microbial taxa as well as 64 serum metabolites. This study identified critical FRGs and their regulatory networks in AD. Potential causal links with microbial and metabolic factors were also uncovered. These findings provide new insights into ferroptosis-mediated mechanisms of AD and suggest promising targets for therapeutic intervention.