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IL6/IL10/TLR4 Govern Immunogenic Cell Death in Aortic Dissection
Yukui Du1, Dongqing Chang1, Bofeng Yu1
1Department of Cardiac Surgery, Center for Cardiac and Panvascular Medicine, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China.
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.
Insights
Programmed cell death (PCD) drives aortic dissection (AD). We identified IL6, IL10, and TLR4 as key biomarkers, revealing immune-vascular crosstalk and potential drug targets for AD therapy.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Aortic dissection (AD) is a critical cardiovascular emergency.
- Programmed cell death (PCD) is implicated in AD pathogenesis, but mechanisms are unclear.
- This study identifies PCD-related biomarkers for novel therapeutic strategies.
Purpose of the Study:
- To systematically investigate programmed cell death (PCD)-related biomarkers in aortic dissection (AD).
- To identify novel therapeutic targets for AD by analyzing molecular drivers of PCD.
Main Methods:
- Integrated multiomics analysis of aortic tissues from AD patients and controls.
- Identified differentially expressed genes (DEmRNAs) and intersected them with programmed cell death-related genes (PCD-RGs).
- Utilized network analysis, immune infiltration profiling, and drug-target prediction to characterize key drivers.
Main Results:
- Identified IL6, IL10, and TLR4 as significant PCD-associated biomarkers in AD.
- Biomarkers are enriched in immunoregulatory pathways, with IL10 correlating strongly with immune cells and endothelial cells.
- Discovered regulatory networks involving transcription factors and miRNAs, and identified 91 potential repurposable drugs.
Conclusions:
- IL6, IL10, and TLR4 are central regulators of PCD in AD pathogenesis.
- Immune-vascular crosstalk and immunogenic cell death are key therapeutic targets for AD.
- The identified biomarker network and drug candidates offer a framework for precision AD therapies.
