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

BACKGROUND: 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. OBJECTIVES: This study aimed to investigate how lipid accumulation influences macrophage activation and subsequent fibroblast responses in keloid-associated inflammation. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.