TY  - EJOU
AU  - Pang, Yiheng 
AU  - Chao, Naixia 
AU  - Li, Hongji 
AU  - Xie, Mingxi 
AU  - Wang, Chunxia 
AU  - Xu, Ge 

TI  - From Limited Samples to Mechanistic Insights: Exploring Ferroptosis-Related Genes in Hypoplastic Left Heart Syndrome
T2  - Structural and Congenital Heart Disease

PY  - 2026
VL  - 21
IS  - 1
SN  - 3071-1738

AB  - <b>Background:</b> Hypoplastic left heart syndrome (HLHS) is a congenital heart disease (CHD), and accumulating evidence has implicated ferroptosis in the pathogenesis of HLHS. Therefore, exploring ferroptosis-related genes (FRGs) in HLHS is of clinical significance. <b>Materials and Methods:</b> Gene Expression Omnibus (GEO) was accessed to obtain analytical data. WGCNA was employed to screen relevant module genes, and the limma package was used to identify differentially expressed genes (DEGs). The rfe function in the R package caret and the glmnet package were utilized to conduct SVM-RFE and LASSO regression analyses, and the intersection of these two analyses was taken as the HLHS-related genes. The reliability of the HLHS-related genes was verified by receiver operating characteristic (ROC) curve. Single-sample GSEA (ssGSEA) was used to calculate the scores of each pathway, and the R package clusterProfiler was employed to perform enrichment analysis on the genes. The NetworkAnalyst was used to predict transcription factors (TFs). <b>Results:</b> WGCNA analysis identified that the module genes were chiefly enriched in inflammation and immunity pathways, especially neutrophil-related module genes. Two HLHS-related genes, Cystathionine β-synthase (<i>CBS</i>) and Heparan-α-glucosaminide N-acetyltransferase (<i>HGSNAT</i>), were obtained. A high area under the curve (AUC) values confirmed the reliability of these two genes as the HLHS-related genes. CHD signaling pathway analysis revealed higher scores in most pathways in control group than HLHS group. Additionally, the score of <i>CBS</i> showed a positive association with hypoxia pathway and VEGF signaling pathway, whereas <i>HGSNAT</i> exhibited a negative association. Ultimately, <i>CBS</i> and <i>HGSNAT</i> shared three TFs, namely JUN, EGR1, and TFAP2A. <b>Conclusion:</b> Collectively, this study identified <i>CBS</i> and <i>HGSNAT</i> as ferroptosis-related candidate biomarkers for HLHS. This study offered new directions for HLHS, contributing to the effective treatment of the disease.
KW  - Hypoplastic left heart syndrome; ferroptosis-related gene; machine learning; signaling pathway; enrichment analysis; transcription factor

DO  - 10.32604/schd.2026.072858