2. Academic Validation
  3. Lonidamine alleviates inflammation and tissue remodeling in a mouse model of eosinophilic chronic sinusitis: A single-cell transcriptomics study

Lonidamine alleviates inflammation and tissue remodeling in a mouse model of eosinophilic chronic sinusitis: A single-cell transcriptomics study

  • Int Immunopharmacol. 2025 Jul 22:163:115258. doi: 10.1016/j.intimp.2025.115258.
Jia Liu 1,  Lei Wu 1,  Hao Wei 2,  Xiang Liu 1,  Chenzhi Zheng 3,  Xinglong Wu 3,  Niancheng Yu 1,  Xin Yang 4,  Yicheng Xie 5,  Yingshuo Wang 6
Affiliations

Affiliations

  • 1 Department of Otolaryngology-Head and Neck Surgery, Pulmonology, Traditional Chinese Medicine, and Genetics and Metabolism, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, 310052 Hangzhou, China.
  • 2 Department of Otolaryngology-Head and Neck Surgery, Pulmonology, Traditional Chinese Medicine, and Genetics and Metabolism, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, 310052 Hangzhou, China; School of Life Sciences, Fudan University, 200438 Shanghai, China.
  • 3 School of Computer Science and Engineering, Hubei Key Laboratory of Intelligent Robot, Wuhan Institute of Technology, 430205 Wuhan, China.
  • 4 Department of Otolaryngology-Head and Neck Surgery, Pulmonology, Traditional Chinese Medicine, and Genetics and Metabolism, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, 310052 Hangzhou, China. Electronic address: yangxinner@zju.edu.cn.
  • 5 Department of Otolaryngology-Head and Neck Surgery, Pulmonology, Traditional Chinese Medicine, and Genetics and Metabolism, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, 310052 Hangzhou, China; School of Life Sciences, Fudan University, 200438 Shanghai, China. Electronic address: ycxie@zju.edu.cn.
  • 6 Department of Otolaryngology-Head and Neck Surgery, Pulmonology, Traditional Chinese Medicine, and Genetics and Metabolism, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, 310052 Hangzhou, China. Electronic address: wangyingshuo@zju.edu.cn.
PMID: 40700828 DOI: 10.1016/j.intimp.2025.115258
Abstract

Background: Eosinophilic chronic sinusitis (ECRS) is a refractory condition resistant to therapies and prone to relapse. Hexokinase 2 (HK2), a key glycolysis enzyme, regulates inflammation but its role in ECRS is unclear.

Methods: An ECRS mouse model was established using intranasal administration of papain. Single-cell RNA Sequencing (scRNA-seq) was employed to analyze the expression patterns of Hk2 in ECRS. The HK2 inhibitor lonidamine (LND) was administered orally to assess symptoms, inflammatory cells and cytokines in the nasal lavage fluid (NALF), serum total IgE, and pathological characteristics of nasal mucosal inflammation. Mechanistic insights were investigated using scRNA-seq and an in vitro human nasal epithelial cells (HNEpC) model stimulated with IL-4, IL-13, and TNF-α.

Results: Elevated Hk2 expression was found in the nasal mucosa in the ECRS model. LND alleviated ECRS symptoms, reducing sneezing, cytokine release, inflammatory cell infiltration, and goblet cell hyperplasia. Epithelial cell damage was identified as a key driver of inflammation and remodeling. LND suppressed inflammation by inhibiting differentiation of inflammatory epithelial cells and neutrophils via Cxcl1-Cxcr2. Additionally, LND reduced epithelial cell-induced nasal mucosal remodeling by inhibiting the Ptn-Ncl signaling pathway between epithelial cells and neurons. In the in vitro experiment, LND significantly and dose-dependently reduced both CXCL1 and PTN expression, confirming its direct anti-inflammatory and anti-remodeling effects on nasal epithelial cells.

Conclusions: LND significantly suppressed nasal inflammation and tissue remodeling in the ECRS model. These findings suggest that HK2 inhibition holds promise as a safe and effective therapeutic approach for the management of ECRS.

Keywords

Eosinophilic chronic rhinosinusitis; Hexokinase 2; Immuno-inflammatory responses.

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