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Identification of ferroptosis-genes associated with pediatric inflammatory bowel disease bioinformatics and machine
Zhen Xu1, Mei Yang2, Chenghao Ou1
1Department of Gastroenterology and Hepatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.
Insights
New biomarkers PML and CHAC1 show promise for early pediatric inflammatory bowel disease (PIBD) diagnosis. These ferroptosis-related genes could improve diagnostic accuracy and inform new therapeutic strategies for PIBD.
Area of Science:
- Gastroenterology
- Cell Biology
- Biomarker Discovery
Background:
- Pediatric inflammatory bowel disease (PIBD) is a growing concern with diagnostic challenges.
- The role of ferroptosis, an iron-dependent cell death, in PIBD pathogenesis is not well understood.
Purpose of the Study:
- Identify ferroptosis-related genes for early PIBD diagnosis.
- Validate the role of these genes in ferroptosis.
Main Methods:
- Analyzed RNA-seq data from PIBD patients using bioinformatics tools (DESeq2, WGCNA).
- Screened diagnostic genes via machine learning algorithms (LASSO, Random Forest, mSVM-RFE).
- Validated findings in vitro using NCM460 cells and in vivo datasets, assessing ferroptosis markers and immune infiltration.
Main Results:
- PML and CHAC1 identified as high-performance biomarkers for PIBD diagnosis (AUC > 0.7).
- Knockdown of PML or CHAC1 reduced ferroptosis in LPS-treated cells.
- Genes associated with immune pathways; ceRNA network revealed regulatory roles.
Conclusions:
- PML and CHAC1 are promising early diagnostic biomarkers for PIBD.
- Findings support improved diagnostic accuracy and offer insights into PIBD's immune microenvironment and potential therapies.
Background:
Pediatric inflammatory bowel disease (PIBD) is increasingly common, and early diagnosis remains challenging due to unclear etiology. Ferroptosis, an iron-dependent form of cell death, may be involved in intestinal inflammation, but its expression and role in PIBD are poorly understood.
Objective:
To identify ferroptosis-related genes as candidate biomarkers for early diagnosis of PIBD and validate their role in ferroptosis.
Methods:
RNA-seq data of PIBD from GEO datasets were analyzed using DESeq2, WGCNA, and functional enrichment analysis. Ferroptosis-related diagnostic genes were screened through LASSO, Random Forest, and mSVM-RFE algorithms, and validated in GSE57945 and GSE117993 datasets. In vitro experiments using NCM460 cells were performed to validate the roles of PML and CHAC1 in LPS-induced ferroptosis, including siRNA-mediated gene knockdown, western blotting of ferroptosis-related proteins (ACSL4, SLC7A11, GPX4, FTH), and measurement of lipid peroxidation (MDA levels). CIBERSORT was used to assess immune cell infiltration, and DGIdb was used to predict potential targeted drugs. A ceRNA network was further constructed to explore miRNA-lncRNA interactions regulating these genes.
Results:
PML and CHAC1 were identified as potential biomarkers for early diagnosis of PIBD, showing high diagnostic performance (AUC > 0.7) in training, validation, and external datasets. In vitro experiments confirmed that knockdown of PML or CHAC1 significantly alleviated LPS-induced ferroptosis in NCM460 cells, as evidenced by restored ferroptosis-related protein expression and reduced MDA accumulation. Consistent with immune infiltration results, both genes were associated with immune-related pathways, and a ceRNA network revealed their potential involvement in complex regulatory mechanisms. DGIdb predicted several candidate drugs targeting these genes.
Conclusion:
PML and CHAC1 are promising biomarkers for early PIBD diagnosis. These findings, supported by both bioinformatic analyses and experimental validation, may improve diagnostic accuracy and provide insights into the immune microenvironment and therapeutic strategies.
