Lipid droplet-mediated macrophage reprogramming drives fibroblast activation in keloid-associated inflammation

Keloids are fibroproliferative skin disorders characterized by excessive collagen deposition and persistent inflammation. Clinical observations reveal their predominant occurrence in sebaceous gland-rich anatomical regions and frequent association with folliculitis, suggesting a potential role for lipid-enriched microenvironments in disease development. However, the molecular mechanisms linking lipid exposure to immune dysregulation in keloid pathogenesis remain poorly understood. This study aimed to investigate how lipid accumulation influences macrophage activation and subsequent fibroblast responses in keloid-associated inflammation. We integrated single-cell RNA sequencing analysis of normal skin, folliculitis, and keloid samples with comprehensive in vitro macrophage-sebocyte co-culture systems and in vivo sebaceous gland hyperplasia models to characterize lipid-mediated immune responses. Single-cell transcriptomic analysis revealed distinct macrophage populations with enhanced lipid metabolism signatures in both folliculitis and keloid samples. Sebaceous lipid exposure induced extensive lipid droplet formation in macrophages through ACSL-dependent pathways, accompanied by functional reprogramming toward a pro-fibrotic phenotype. This transformation was accompanied by upregulation of transcription factors MafB and Maf, independent of canonical IL-4/STAT6 signaling. Macrophages with enhanced lipid droplet formation subsequently promoted fibroblast proliferation, enhanced collagen synthesis, and facilitated extracellular matrix remodeling through the CXCL8 signaling axis. In vivo validation using a sebaceous gland hyperplasia model confirmed increased collagen deposition and α-SMA expression associated with MafB+Maf+CD206+ macrophage accumulation. Our findings reveal that lipid droplet-mediated macrophage activation represents an important mechanism linking sebaceous lipid-rich microenvironments to fibrotic responses in keloid-associated inflammation. The identification of MafB- and Maf-regulated transcriptional programs and CXCL8-dependent macrophage-fibroblast crosstalk provides new therapeutic targets for preventing and treating keloid disorders.