Comprehensive analysis of keloid super-enhancer networks reveals FOXP1-mediated anti-senescence mechanisms in fibrosis.

There is a significant gap in multi-omics studies on keloids, especially concerning the interaction between fibroblasts and super-enhancers (SEs). Identifying novel biomarkers within the epigenetic landscape could greatly improve keloid management. In this study, we investigated gene expression at both transcriptional and translational levels to identify potential biomarkers and employed CUT&Tag technology to validate SE-associated genes and upstream transcription factors (TFs). Through integrated analyses of transcriptomics and proteomics, 10 hub genes that associated with ECM, immune, and metabolic pathways were found. Given the crucial role of fibroblasts in keloid pathogenesis, we further identified five SE-associated genes (SERPINH1 SE, MMP14 SE, COL5A1 SE, COL16A1 SE, and SPARC SE) that exhibit characteristic upregulation in keloids. Analysis of upstream TFs and core transcription regulatory circuitry (CRC) revealed potential master TFs (FOSL2, BACH2, and FOXP1), with FOXP1 emerging as the core TF likely driving pro-fibrotic development through its anti-senescence function. In summary, we anticipate that the outcomes of the integrative omics analysis will facilitate further investigation into the underlying molecular mechanisms of keloid formation and lead to novel strategies for its prevention and management. Specifically inhibiting the anti-senescence function of FOXP1 brings new promise for the treatment of fibrosis-related diseases.