Knockdown of S100A9 inhibits pyroptosis and promotes PPAR signaling pathway in atopic dermatitis

  • Biochem Biophys Res Commun. 2025 Sep 12:779:152431. doi: 10.1016/j.bbrc.2025.152431.
Lei Li  1 ,  Minghui Yu  1 ,  Tingting Zheng  2 ,  Lijuan Hu  3
Affiliations
  • 1. Department of Allergic Reaction, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan City, Shanxi Province, 030032, China.
  • 2. Department of Cardiovascular Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan City, Shanxi Province, 030032, China.
  • 3. Department of Emergency Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan City, Shanxi Province, 030032, China. Electronic address: [email protected].
PMID: 40773921 DOI: 10.1016/j.bbrc.2025.152431
Abstract

Background: Atopic dermatitis (AD) is a common chronic and relapsing inflammatory skin disease. Although its clinical and pathological characteristics are well documented, the underlying molecular mechanisms remain incompletely elucidated.

Methods: Hub differentially expressed genes (DEGs) in AD were identified using the GSE222771 and GSE182740 datasets. Cytokine (TNF-α/IFN-γ)-stimulated HaCaT cells and 2,4-dinitrochlorobenzene (DNCB)-induced AD-like mouse models were established to mimic inflammatory conditions in vitro and in vivo. Inflammatory cytokine levels and pyroptosis-related protein expression were quantified by enzyme-linked immunosorbent assay (ELISA) and Western blot, respectively. To investigate the role of S100 calcium-binding protein A9 (S100A9) in AD, both S100A9 knockdown and treatment with the selective S100A9 inhibitor paquinimod were employed. To assess the involvement of the Peroxisome Proliferator-activated Receptor (PPAR) signaling pathway, specific inhibitors targeting PPARα (MK886) and PPARγ (GW9662) were administered.

Results: S100A7A, SERPINB4, KRT16, and S100A9 were identified as potential diagnostic biomarkers for AD, with their expression markedly upregulated in IFN-γ/TNF-α-stimulated HaCaT cells. Knockdown of S100A9 attenuated inflammatory responses and suppressed Pyroptosis, as evidenced by reduced levels of cleaved Caspase-1, GSDMD-N, and NLRP3. S100A9 deficiency alleviated skin lesions and decreased mast cell infiltration in DNCB-induced AD-like mice. S100A9 inhibitor paquinimod promoted the expression of PPAR-α and PPAR-γ protein levels. MK886 and GW9662 significantly reversed the inhibitory effects of S100A9 knockdown on inflammatory responses and Apoptosis.

Conclusion: S100A9 knockdown inhibits Pyroptosis and stimulates the PPAR signaling pathway in AD, which offers a potential strategy for AD treatment.

Keywords
Atopic dermatitis; PPAR signaling pathway; Pyroptosis; S100A9.
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