Targeting PDCD4 in cancer and atrial fibrillation: mechanistic insights from integrated multi-omics and single-cell analysis.

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.