Genistein alleviates skin inflammation in atopic dermatitis by inhibiting mast cell degranulation through toll-like receptor

  • Phytomedicine. 2026 Jul 25:157:158308. doi: 10.1016/j.phymed.2026.158308.
Hongfen Du  1 ,  Na Wang  2 ,  Chao Wang  3 ,  Shiqiong Luo  3 ,  Xiaolan Ji  3 ,  Rui Li  3 ,  Yuejin Wang  3 ,  Xiurong Lai  3 ,  Henan Li  3 ,  Yuanyuan Ding  4 ,  Hongli An  5
Affiliations
  • 1. Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; College of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
  • 2. Department of Otolaryngology, Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China.
  • 3. College of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
  • 4. College of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. Electronic address: [email protected].
  • 5. Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. Electronic address: [email protected].
PMID: 42184496 DOI: 10.1016/j.phymed.2026.158308
Abstract

Background: Atopic dermatitis (AD) is a mast cell-driven inflammatory disorder with limited treatment options. This study aimed to explore the therapeutic potential and mechanism of the natural compound genistein against AD.

Objective: We investigated the efficacy of genistein treatment on atopic dermatitis and the underlying immune mechanism of cytokine release by mast cell.

Methods: We employed an MC903-induced murine AD model and LAD2 human mast cells. Evaluations included behavioral assessment, serological, histopathology, mast cell degranulation assays, RNA-seq, molecular docking, SPR, pathway analysis, and functional validation via TRAM mutagenesis and rescue experiments.

Results: Genistein alleviated ear thickening and scratching behavior, reduced the spleen-to-body weight ratio, decreased serum levels of IgE and IL-4 in the AD model, and significantly suppressed mast cell degranulation. Transcriptomic analysis provided evidence that genistein alleviated AD symptoms through the mast cell and TLR signaling pathways. Genistein markedly inhibited the occurrence of systemic allergic reactions and local inflammation; suppressed the release of β-hexosaminidase, histamine, MCP-1, tryptase, TNF-α, and calcium in LAD2 cells. Mechanistically, genistein directly binding to the D127 and R226 sites of TRAM with high affinity (Kᴅ = 0.491 µM), played as the inhibitor of TRAM, a key molecule in the TLR signaling pathway in mast cells, thereby suppressing activation of the NF-κB signaling pathway.

Conclusion: Our findings demonstrate that genistein alleviates AD by specifically targeting the D127 and R226 sites of TRAM to inhibit mast cell activation via the PLCγ1-IKKβ-NF-κB pathway. This work elucidates a novel pharmacological mechanism of a natural compound and identifies TRAM as a promising new therapeutic target for allergic inflammatory diseases, highlighting the value of natural products in developing targeted immunomodulatory therapies.

Keywords
Atopic dermatitis; Genistein; Mast cells; NF-κB signaling pathway; TRAM.
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