Micheliolide directly targets keratinocyte Annexin A2 to abrogate STAT3-driven inflammation and pruritus in atopic...

The limited understanding of keratinocyte-intrinsic pathways that drive and sustain inflammation in atopic dermatitis (AD) has hindered the development of targeted therapies.

This study aimed to identify a novel, druggable signaling hub in AD keratinocytes and to discover a natural compound capable of therapeutically targeting this pathway.

We performed an unbiased transcriptomic analysis of human and murine AD datasets. Functional validation employed MC903-induced AD mouse models with keratinocyte-specific gene silencing. Candidate compounds were identified via virtual screening of natural product libraries, with direct target binding confirmed by cellular thermal shift assay (CETSA), molecular docking, and pull-down assay. Mechanistic insights were gained through western blot, immunofluorescence, and gene expression analyses in primary mouse and human keratinocytes.

We identified Annexin A2 (ANXA2) as a consistently upregulated hub gene in AD keratinocytes. Its keratinocyte-specific silencing potently alleviated AD pathology, including inflammation, pruritus, and epidermal hyperplasia. Mechanistically, ANXA2 acts as an essential upstream regulator of STAT3 phosphorylation, forming a critical axis in AD. Virtual screening identified the natural compound Micheliolide (MCL) as a direct ANXA2 binder. MCL treatment effectively suppressed the ANXA2-STAT3 pathway and ameliorated AD pathology in vivo.

Our work identifies the ANXA2-STAT3 axis as a novel pathogenic driver in AD and highlights MCL as a promising natural therapeutic targeting this keratinocyte-intrinsic inflammatory pathway.