FOSL1-mediated super-enhancer facilitates pathological scarring

Abnormal wound healing leads to pathological scar formation, characterized by excessive fibrosis. Despite their clinical relevance, the underlying molecular factors remain poorly understood. Using single-cell RNA sequencing, we identify FOSL1⁺ keratinocyte subpopulations that expand in hypertrophic scars and keloids. These cells exhibit epithelial-mesenchymal transition features and promote fibrosis by secreting MMP3, a critical mediator of fibroblast activation. Mechanistically, FOSL1 drives MMP3 transcription by engaging a MED-1 associated super-enhancer, amplifying fibroblast activation and inflammation. Importantly, the FOSL1 inhibitor SR11302 reduces scar formation in in vivo xenogenic keloid models, offering a potential therapeutic strategy. Collectively, this study elucidates abnormal tissue repair mechanisms driven by aberrant cellular interactions, providing a theoretical foundation for developing intervention strategies toward scarless healing.