Genkwanin reduces airway epithelial cell ferroptosis and alleviates asthma symptoms in mice

IF 8.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-09-24 DOI:10.1016/j.phymed.2025.157306

Xun Chen , Jing Liu , Zimeng An , Min Li , Xiaohua Ji , Jing Huang , Xiaoru Yan

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引用次数: 0

Abstract

Background

This study investigated the role of genkwanin (GKA) in pediatric asthma.

Methods

Newborn mice were exposed to house dust mites and treated with GKA to examine airway epithelial cell damage and airway remodeling. The targets of GKA were predicted and verified.

Results

After medium-dose GKA (M-GKA) treatment, HDM-IgE, HDM-IgG1, IL-5, IL-13, and IL-4 decreased by 28 %, 22 %, 32 %, 48 %, and 38 %, respectively. M-GKA reduced collagen formation by 28 % and MUC5AC protein expression by 30 % in mice. M-GKA reduced Fe2+ content by 32 % and ROS levels by 21 % in airway epithelial cells by inhibiting DYRK1A activity. DYRK1A increased TFE3 cytoplasmic retention by 73 % through enhancing its serine phosphorylation (by 133 %), leading to suppression of LC3BII/I and ATG5 by 32 % and 37 %, and promotion of MDA content by 263 % and ROS accumulation by 43 %. TFE3 triggered autophagy to mitigate ferroptosis (Fe2+ and ROS contents were decreased by 59 % and 25 %, while GPX4 and SLC7A11 were downregulated by 104 % and 88 %). TFE3 knockout weakened the alleviation of airway epithelial cell ferroptosis by GKA, as evidenced by increased Fe2+ content (89 %), MDA and ROS accumulation (73 % and 44 %, respectively). Additionally, it blocked autophagy, as indicated by decreased LC3B (58 %) and ATG5 (51 %) expression.

Conclusions

GKA inhibits TFE3 phosphorylation via DYRK1A, thereby driving TFE3 nuclear translocation and activating autophagy, which suppresses ferroptosis in airway epithelial cells. This study identifies GKA as a therapeutic candidate for asthma, and screening of additional flavones will be valuable to map the structural features that confer this activity.

Abstract Image

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根宽万素减轻小鼠气道上皮细胞铁下垂，减轻哮喘症状

本研究旨在探讨根管素（GKA）在儿童哮喘中的作用。方法将新生小鼠暴露于室内尘螨后，用GKA处理，观察其气道上皮细胞损伤和气道重塑。对GKA的靶点进行了预测和验证。结果中剂量GKA （M-GKA）治疗后，HDM-IgE、HDM-IgG1、IL-5、IL-13、IL-4分别降低28%、22%、32%、48%、38%。M-GKA使小鼠的胶原形成减少28%，MUC5AC蛋白表达减少30%。M-GKA通过抑制DYRK1A活性，使气道上皮细胞中Fe2+含量降低32%，ROS水平降低21%。DYRK1A通过增强其丝氨酸磷酸化使TFE3细胞质保留增加了73%（增加了133%），导致LC3BII/I和ATG5抑制32%和37%，促进MDA含量增加263%，ROS积累增加43%。TFE3触发自噬减轻铁下垂（Fe2+和ROS含量分别下降59%和25%，GPX4和SLC7A11下调104%和88%）。TFE3敲除减弱了GKA对气道上皮细胞铁下垂的缓解，这可以从Fe2+含量（89%）、MDA和ROS积累（分别为73%和44%）的增加中得到证明。此外，它还能阻断自噬，LC3B（58%）和ATG5（51%）表达降低。结论sgka通过DYRK1A抑制TFE3磷酸化，从而驱动TFE3核易位，激活自噬，抑制气道上皮细胞铁下垂。这项研究确定了GKA作为哮喘的治疗候选药物，筛选额外的黄酮将对绘制赋予这种活性的结构特征有价值。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.