Study on the Potential Molecular Mechanism of Keloid Disease Associated With Single Cell Combined Mendelian Randomization

<h4>Background</h4>Keloids are pathological scars with incompletely understood pathogenesis. This study aims to identify the key genes and regulatory networks potentially involved in keloid formation by integrating single-cell transcriptomics (scRNA-seq), protein quantitative trait loci (pQTL), Mendelian randomization (MR) analyses, colocalization, and comprehensive functional characterization.<h4>Methods</h4>Single-cell RNA sequencing data (GSE181297, GSE163973) and bulk transcriptomic data (GSE145725) were obtained from the GEO database. These datasets, which included both keloid lesions and normal scar samples from distinct individuals, were subjected to rigorous quality control and cell annotation. Intercellular communication was analyzed using CellChat, and co-expression networks were constructed via hdWGCNA. To identify potential causal genes, MR analysis was performed by integrating pQTL data from the deCODE database with GWAS summary statistics (GCST90018874), followed by colocalization, sensitivity analysis, and reverse validation. Further functional characterization of potential key genes was conducted through Gene Set Enrichment Analysis (GSEA), immune infiltration analysis, transcription factor (TF) regulatory network inference, and pseudotime trajectory analysis.<h4>Results</h4>92 659 high-quality cells were retained, revealing seven major cell types with fibroblasts showing the most extensive intercellular interactions. Mendelian randomization identified 11 genes causally linked to keloid risk, with genetically determined downregulation of SSR1 and SRA1 associated with increased susceptibility. SRA1 was enriched in cell cycle, nucleocytoplasmic transport, and ribosome biogenesis in eukaryotes, while SSR1 was implicated in complement/coagulation cascades, the NOD-like receptor signaling pathway, and viral protein interaction with cytokine and cytokine receptors. Immunoinfiltration, TF network and motif analysis, and pseudotime analysis further characterized their regulatory roles in immune microenvironment modulation and cell differentiation.<h4>Conclusions</h4>This multi-omics study identifies SRA1 and SSR1 as potential key protective genes in keloid pathogenesis. These genes may contribute to inhibiting disease progression through modulation of cell proliferation, the immune microenvironment, and cellular signaling pathways. These findings provide novel mechanistic insights and potential immunotherapeutic targets for keloids.