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Targeting PDCD4 in cancer and atrial fibrillation: mechanistic insights from integrated multi-omics and single-cell
Juledezi Hailati1, Zhiqiang Liu1, Lei Zhang1
1Cardiovascular Disease Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Background:
Atrial fibrillation (AF) is a complicated and varied cardiovascular disorder with inadequate understanding of its molecular underpinnings. While Programmed cell death factor 4 (PDCD4) has been associated in several illnesses, its particular significance in AF remains unknown. This work seeks to discover PDCD4-associated critical genes and clarify their regulation processes.
Method:
We built a protein-protein interaction (PPI) network to emphasize important biological interactions and used transcriptome analysis to find differentially expressed genes (DEGs). Regulatory mechanisms were explored through miRNA-mRNA and transcription factor (TF) analysis. Single-cell RNA sequencing (SCRNA-SEQ) data were utilized to identify crucial cell types and intercellular communication patterns associated with key genes.
Results:
qRT-PCR analysis of peripheral blood mononuclear cells (PBMCs) from AF patients and healthy controls revealed a significant upregulation of PDCD4 in AF patients. Through differential expression analysis and PPI network construction, 11 key genes were identified. In addition, mmu-miR-429-3p regulates Sirt1 while Wt1 shares regulatory roles with PDCD4, Wasl, and Abl2, and that Sirt1 and Atad5 are both regulated by Thap9. Drug prediction analyses revealed sirtinol and trichostatin as promising therapeutic drugs for targeting Atad5 and Sirt1, respectively, with good molecular docking scores (< -5 kcal/mol). SCRNA-SEQ data pinpointed arterial and venous endothelial cells as critical cell types associated with the key genes. Finally, we also found that PDCD4 dysregulation in cancers like ACC may increase AF risk through immune modulation, suggesting that targeting PDCD4 could benefit both AF and ACC patients.
Conclusions:
This study demonstrates that PDCD4 modulates AF progression by regulating key genes and pathways involved in inflammation, fibrosis, and metabolic processes. Insights from transcriptome and single-cell analysis give a full knowledge of the molecular processes underlying AF and indicate PDCD4 as a possible therapeutic target.
Insights
Programmed cell death factor 4 (PDCD4) is upregulated in atrial fibrillation (AF), modulating disease progression via key genes. Targeting PDCD4 may offer therapeutic benefits for both AF and cancer patients.
Area of Science:
- Cardiovascular Biology
- Molecular Oncology
- Systems Biology
Background:
- Atrial fibrillation (AF) is a complex cardiovascular disorder with poorly understood molecular mechanisms.
- The role of Programmed cell death factor 4 (PDCD4) in AF pathogenesis is currently unknown.
- This study investigates PDCD4-associated genes and regulatory pathways in AF.
Purpose of the Study:
- To identify critical genes associated with PDCD4 in atrial fibrillation.
- To elucidate the regulatory mechanisms involving PDCD4 in AF.
- To explore potential therapeutic targets for AF based on PDCD4 pathways.
Main Methods:
- Protein-protein interaction (PPI) network construction and transcriptome analysis to identify differentially expressed genes (DEGs).
- MicroRNA (miRNA)-mRNA and transcription factor (TF) analyses to explore regulatory networks.
- Single-cell RNA sequencing (scRNA-seq) to identify key cell types and intercellular communications.
Main Results:
- PDCD4 was significantly upregulated in peripheral blood mononuclear cells (PBMCs) of AF patients.
- Eleven key genes were identified through differential expression and PPI network analysis.
- Regulatory relationships were uncovered, including mmu-miR-429-3p targeting Sirt1, and PDCD4 sharing regulatory roles with other genes. Sirt1 and Atad5 are regulated by Thap9.
- Drug prediction identified sirtinol and trichostatin as potential therapeutics for Atad5 and Sirt1.
- scRNA-seq identified arterial and venous endothelial cells as critical cell types.
- PDCD4 dysregulation in cancers like adrenocortical carcinoma (ACC) may increase AF risk via immune modulation.
Conclusions:
- PDCD4 plays a role in AF progression by regulating inflammation, fibrosis, and metabolic pathways.
- Transcriptome and single-cell analyses provide comprehensive insights into AF molecular processes.
- PDCD4 emerges as a potential therapeutic target for atrial fibrillation.
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