Luteolin Disrupts Keratinocyte-Dendritic Cell Communication in Psoriasis by Targeting Rh Family C Glycoprotein

Psoriasis, a chronic inflammatory skin disease, arises from a dysregulated interaction between keratinocytes (KCs) and dendritic cells (DCs). We previously identified Rh family C glycoprotein (RHCG) as a key mediator of KC inflammation and DC activation. Here, we demonstrate that luteolin, a bioactive compound derived from the traditional Chinese formula cooling blood and detoxicating formula (CBDF), directly binds to RHCG, as confirmed by multiple computational methods and in vitro experiments. In vitro, luteolin suppressed RHCG expression in KCs, reducing CXCL14 secretion and subsequent DC activation. Spatial transcriptomics (STs) revealed that luteolin preferentially targets DC-enriched spatial domains and restores desmosomal protein expression (e.g., DSC2), which is dysregulated in psoriasis. In vivo, luteolin ameliorated psoriasis-like inflammation in imiquimod-induced mice, lowering Psoriasis Area and Severity Index (PASI) scores and normalizing pathological markers. Our findings indicate that luteolin disrupts KC-DC communication through multiple modes of action, thereby reversing tissue-level pathology and demonstrating its potential as a targeted therapy for psoriasis.