Lumican-mediated fibroblast differentiation in skin fibrosis.

While fetal skin achieves scarless healing, the molecular mechanisms underlying this regenerative capacity remain incompletely characterized. This study integrates single-cell RNA sequencing with spatial transcriptomics to investigate fibroblast-mediated tissue repair. A comparative analysis of fetal skin (FS), adult skin (AS), and keloid tissue was performed to investigate fibroblast gene expression profiles, subpopulation heterogeneity, and differentiation trajectories. Cross-tissue intersection of fibroblast differentially expressed genes (DEGs) from AS vs. FS and keloid vs. AS identified candidate regulators associated with the continuum from scarless healing to pathological fibrosis. FS showed distinct metabolic activation and pro-regenerative fibroblast subpopulations, contrasting with fibrotic phenotypes in AS and keloids. Integrative analysis identified five hub genes (BGN, COL6A1, FN1, LUM, TIMP1) progressively upregulated from FS to AS and keloids. Lumican, the protein encoded by LUM, demonstrated fibroblast-specific expression and was positively correlated with fibroblast differentiation trajectories associated with fibrosis. Functional validation revealed that Lumican knockdown reversed keloid fibroblast differentiation, suppressed collagen deposition, and attenuated fibrosis. This was confirmed using 3D human keloid organoid and nude mouse models. This study suggests that Lumican functions as a regulator of fibroblast differentiation, bridging regenerative healing and pathological scarring. Targeting Lumican may represent a potential therapeutic approach to inhibit fibrosis and promote scarless repair.