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

  • Phytomedicine. 2026 Jul 25:157:158303. doi: 10.1016/j.phymed.2026.158303.
Yuqi Zhang  1 ,  Ji-An Wang  2 ,  Long-Fei Li  3 ,  Xue-Wen Chen  2 ,  Qun-Feng Gui  4 ,  Cheng He  1 ,  Yubo Zhu  1 ,  Ye Tao  1 ,  Jian-Feng Meng  4 ,  Meng-Ruo Song  4 ,  Rong Sun  1 ,  Juan Wang  1 ,  Jian-Shuang Guo  5 ,  Su Liu  6 ,  Zhi-Jun Zhang  7
Affiliations
  • 1. Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, 226001, China; Department of Human Anatomy, Medical School of Nantong University, Nantong, Jiangsu, 226001, China.
  • 2. Department of Dermatologic Surgery, Shanghai Skin Disease Hospital, Tongji University, Shanghai, 200443, China.
  • 3. College of Pharmaceutical Sciences, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding, Hebei, 071002, China.
  • 4. Department of Neurosurgery, the Sixth Affiliated Hospital of Nantong University, Yancheng Third People's Hospital, Yancheng, Jiangsu, 224008, China.
  • 5. College of Pharmaceutical Sciences, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding, Hebei, 071002, China. Electronic address: [email protected].
  • 6. Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, 226001, China. Electronic address: [email protected].
  • 7. Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, 226001, China; Department of Human Anatomy, Medical School of Nantong University, Nantong, Jiangsu, 226001, China; Jiangsu Province Key Laboratory in University for Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu, 226001, China. Electronic address: [email protected].
PMID: 42172985 DOI: 10.1016/j.phymed.2026.158303
Abstract

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

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords
ANXA2; Atopic dermatitis; Keratinocytes; MC903; Micheliolide; STAT3 signaling.
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