LCN2 ‐Driven Fibroblast Ferroptosis‐Associated Injury Promotes Keratinocyte Proliferation via Lipid Peroxidation Signaling in Psoriasis

ABSTRACT

Psoriasis is a chronic inflammatory skin disorder in which biologics targeting immune pathways have markedly improved clinical outcomes. Nevertheless, persistent oxidative stress and stromal abnormalities in lesional skin indicate that pathogenic mechanisms beyond canonical immune circuits remain active. Here, we integrated single‐cell RNA sequencing, an imiquimod (IMQ)‐induced psoriasiform murine model, LC–MS/MS‐based metabolomic profiling of fibroblast‐conditioned medium, and complementary in vitro studies to define ferroptosis‐related alterations in dermal fibroblasts under psoriasis‐like inflammatory conditions. Single‐cell analysis revealed a marked expansion of an inflammatory fibroblast subset (iFb1) in psoriasiform lesions, together with enrichment of ferroptosis‐related pathways. In vivo and in vitro analyses further showed that inflammatory stimulation induced ferroptosis‐related injury in dermal fibroblasts, as evidenced by increased lipid peroxidation, impaired antioxidant defenses, and characteristic ultrastructural alterations. Metabolomic profiling of conditioned medium further indicated secretory remodeling characterized by enrichment of lipid mediators and redox‐associated metabolites. Lipocalin‐2 (LCN2) was significantly upregulated in psoriasis‐associated fibroblasts and exacerbated lipid peroxidation and ferroptosis‐related injury. Conditioned medium from inflammation‐stimulated fibroblasts enhanced keratinocyte proliferation, whereas inhibition of fibroblast ferroptosis or LCN2 knockdown attenuated this effect. Further experiments suggested that 4‐hydroxy‐2‐nonenal (4‐HNE) may act as a potential mediator of fibroblast–keratinocyte crosstalk. Topical administration of carnosine, a potent 4‐HNE scavenger, alleviated IMQ‐induced psoriasiform skin lesions in vivo. Together, these findings support an LCN2‐driven fibroblast–keratinocyte crosstalk axis linked to ferroptosis‐related injury in psoriasis and highlight stromal lipid peroxidation as a potential therapeutic target.