IL6/IL10/TLR4 Govern Immunogenic Cell Death in Aortic Dissection.

BACKGROUND

Aortic dissection (AD), a life-threatening cardiovascular emergency, poses a significant threat to global cardiovascular health. Emerging evidence implicates programmed cell death (PCD) as a critical driver of AD pathogenesis, yet the molecular mechanisms remain poorly defined. This study systematically investigates PCD-related biomarkers in AD to identify novel therapeutic targets.

METHODS

Multiomics analysis integrated transcriptome sequencing data from eight AD and five control aortic tissues. Differentially expressed genes (DEmRNAs, n = 3094) were intersected with 1574 programmed cell death-related genes (PCD-RGs) to identify candidate biomarkers. Protein-protein interaction (PPI) networks, functional enrichment, immune infiltration profiling, and drug-target prediction were employed to characterize key molecular drivers.

RESULTS

Three PCD-associated biomarkers were identified: IL6 (11.8-fold upregulated), IL10 (26.1-fold upregulated), and TLR4 (0.38-fold downregulated). These biomarkers exhibited significant enrichment in immunoregulatory pathways including "MYC Targets V1" (FDR < 0.05), with IL10 showing strong immune microenvironment correlations (memory B cells: r = 0.62; endothelial cells: r = -0.58). Regulatory network analysis revealed 58 transcription factors (STAT1/SP1/IRF8) and six key miRNAs (e.g., miR-204-5p) orchestrating biomarker expression. Drug-target mapping identified 91 repurposable agents, including etanercept-szzs (dual IL6/IL10 inhibitor) and TLR4-modulating compounds.

CONCLUSION

This study establishes IL6, IL10, and TLR4 as central regulators of PCD-mediated AD pathogenesis, implicating immune-vascular crosstalk and immunogenic cell death as therapeutic entry points. The identified biomarker network and drug candidates provide a translational framework for developing precision therapies against AD.