Imperatorin Mitigates Rosacea‐Like Inflammation by Modulating the Crosstalk Between <scp>JNK1</scp> and <scp>STAT1</scp>

Rosacea is a chronic inflammatory dermatological disorder involving the activation of various signaling pathways. Imperatorin (IMP), a coumarin compound, has been documented to exhibit anti-inflammatory properties. Nevertheless, its therapeutic efficacy in managing rosacea remains unexplored. Bioinformatics and network pharmacology approaches were utilized to elucidate potential signaling pathways and molecular targets of IMP in the context of rosacea. Subsequently, to assess the in vivo therapeutic efficacy of IMP, murine models exhibiting rosacea-like inflammatory responses were developed. Additionally, in vitro experiments were conducted to elucidate the molecular mechanisms underlying the anti-rosacea effects of IMP. Our findings demonstrated that both intraperitoneal and topical administration of IMP significantly attenuated skin inflammation in mice with LL37-induced rosacea models. Mechanistic investigations, guided by bioinformatics and network pharmacology analyses, revealed an interaction between JNK1 and STAT1. IMP was found to directly bind to JNK1 and STAT1, disrupting their interaction, thereby inhibiting STAT1 phosphorylation and nuclear translocation. This inhibition resulted in decreased production of STAT1-mediated inflammatory mediators in keratinocytes. These results suggest that IMP may serve as a promising therapeutic agent for inflammatory skin diseases by targeting the crosstalk between JNK1 and STAT1.