PRKCB, NLRC4, and TNFSF10 identified as key regulators of lipid metabolism-autophagy network in atherosclerosis

Atherosclerosis (AS), a chronic inflammatory disease, is driven by dysregulated lipid metabolism and impaired autophagy, leading to plaque formation and cardiovascular events. Current treatments often target lipid levels but may not fully address the complex interplay with inflammation and cellular dysfunction. A critical gap remains in identifying the precise genetic regulators that orchestrate the lipid metabolism-autophagy network within the diverse immune microenvironment of AS plaques, which could unlock novel diagnostic and therapeutic strategies. Understanding these key genes and their cellular distribution is crucial for developing more targeted interventions.

Researchers integrated bulk and single-cell RNA sequencing data to identify differentially expressed genes (DEGs) in atherosclerosis. They used weighted gene co-expression network analysis (WGCNA) to pinpoint gene modules linked to lipid metabolism and autophagy. Core regulatory genes were further refined using the machine learning LASSO regression algorithm. Immune cell infiltration characteristics were assessed via ssGSEA for 28 subtypes, and correlations with the three core genes (PRKCB, NLRC4, TNFSF10) were analyzed. Single-cell data determined gene distribution across cell subtypes. Potential drugs targeting these genes were screened from public databases, with molecular docking simulating binding to PRKCB. Finally, gene expression in mouse aortic tissues was validated by RT-qPCR, Western blotting, and IHC, while TNFSF10 levels in mouse plasma were measured by ELISA.

The study successfully identified three core lipid metabolism-autophagy regulatory genes: PRKCB, NLRC4, and TNFSF10. These genes were found to be significantly associated with the immune microenvironment within atherosclerotic plaques. Specifically, they exhibited distinct cell subpopulation distribution patterns, suggesting specialized roles within the complex cellular landscape of AS. The analysis revealed that these genes are involved in the intricate cross-talk between lipid handling and autophagic processes.

PRKCB, NLRC4, and TNFSF10 were identified as key regulators of the lipid metabolism-autophagy network in atherosclerosis, with significant associations to the immune microenvironment. Further validation in mouse aortic tissues confirmed the expression of these target factors through RT-qPCR, Western blotting, and IHC analyses. Additionally, TNFSF10 levels were confirmed in mouse plasma via ELISA, reinforcing its potential as a circulating biomarker. The molecular docking simulations also provided preliminary insights into potential drug interactions with PRKCB, indicating avenues for future therapeutic development.