FUNDC1 mediated mitochondria-dependent ferroptosis of epithelial cells in model of asthma by FBXL2/ar/GPX4 signaling pathway of SUMO1 at K136

This study aimed to explore the critical role of FUNDC1 on epithelial cells in model of asthma. Patients with asthma and normal healthy volunteers were obtained from our hospital. The serum of FUNDC1 mRNA expression was down-regulated in patients with asthma. Meanwhile, the serum of FUNDC1 mRNA expression was positive correlation with IgE and anti-HDM IgE protein. FUNDC1 expression in lung tissue of mice model was decreased in mice model of asthma. Sh-FUNDC1 enhanced asthma in mice model of asthma. FUNDC1 up-regulation reduced IL-4, IL-5, IL-10 and IL-13 activity levels <i>in vitro</i> model of asthma.FUNDC1 down-regulation promoted IL-4, IL-5, IL-10 and IL-13 activity levels <i>in vitro</i> model of asthma. FUNDC1 reduced ferroptosis of epithelial cells in model of asthma through the inhibition of mitochondrial damage. FUNDC1 induced FBXL2 and AR protein expression in model of asthma. FUNDC1 interlinked with FBXL2 is modified by SUMO1 at K136. FBXL2, ASN-205, GLN-204, ARG-235, and GLN-237 form hydrogen bonds with FUNDC1's ASP-15, ASP-16, GLU-25, and ARG-29, with lengths of 2.3, 3.1, 2.9, 2.3, and 2.9 Å, respectively. The induction of FBXL2 reduced the effects of Sh-FUNDC1 on asthma in mice model of asthma. The inhibition of AR reduced the effects of Sh-FUNDC1 on asthma in mice model of asthma Overall, FUNDC1 prevents ferroptosis of airway epithelial cells of asthma through FBXL2/AR/GPX4 signaling pathway of SUMO1 at K136. FUNDC1 might benefit the treatment of asthma or other pulmonary disease. FUNDC1 prevents ferroptosis of airway epithelial cells of asthma through FBXL2/AR/GPX4 signaling pathway of SUMO1 at K136. FUNDC1 might benefit the treatment of asthma or other pulmonary disease.

本研究旨在探究FUN14结构域包含蛋白1（FUNDC1）在哮喘模型上皮细胞中的关键作用。本研究从本院招募哮喘患者与健康对照志愿者。哮喘患者血清中FUNDC1 mRNA的表达水平显著下调。与此同时，哮喘患者血清中FUNDC1 mRNA的表达水平与免疫球蛋白E（IgE）及抗屋尘螨（HDM）IgE蛋白水平呈正相关。哮喘小鼠模型肺组织中FUNDC1的表达水平亦显著降低。靶向FUNDC1的短发夹RNA（sh-FUNDC1）可加重哮喘小鼠模型的病情。在体外哮喘模型中，FUNDC1过表达可降低白细胞介素4（IL-4）、白细胞介素5（IL-5）、白细胞介素10（IL-10）及白细胞介素13（IL-13）的活性水平。而在体外哮喘模型中，FUNDC1低表达则可升高上述细胞因子的活性水平。在哮喘模型中，FUNDC1可通过抑制线粒体损伤，减少上皮细胞的铁死亡（ferroptosis）发生。在哮喘模型中，FUNDC1可诱导F-box亮氨酸丰富重复蛋白2（FBXL2）与雄激素受体（AR）蛋白的表达。与FBXL2结合的FUNDC1可在第136位赖氨酸（K136）位点被小泛素样修饰物1（SUMO1）修饰。FBXL2上的天冬酰胺205（ASN-205）、谷氨酰胺204（GLN-204）、精氨酸235（ARG-235）及谷氨酰胺237（GLN-237）可分别与FUNDC1的天冬氨酸15（ASP-15）、天冬氨酸16（ASP-16）、谷氨酸25（GLU-25）及精氨酸29（ARG-29）形成氢键，键长分别为2.3、3.1、2.9、2.3及2.9埃（Å）。过表达FBXL2可逆转sh-FUNDC1对哮喘小鼠模型的致病作用。抑制AR的表达亦可削弱sh-FUNDC1对哮喘小鼠模型的致病影响。综上，FUNDC1可通过第136位赖氨酸位点SUMO1修饰介导的FBXL2/AR/谷胱甘肽过氧化物酶4（GPX4）信号通路，抑制哮喘气道上皮细胞的铁死亡。FUNDC1有望为哮喘及其他肺部疾病的治疗提供新的思路。FUNDC1可通过第136位赖氨酸位点SUMO1修饰介导的FBXL2/AR/谷胱甘肽过氧化物酶4（GPX4）信号通路，抑制哮喘气道上皮细胞的铁死亡。FUNDC1有望为哮喘及其他肺部疾病的治疗提供新的思路。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于FUNDC1在哮喘模型中的分子机制研究，通过分析哮喘患者和小鼠模型的数据，发现FUNDC1通过抑制线粒体损伤和铁死亡，减轻哮喘症状，其作用涉及FBXL2/AR/GPX4信号通路和SUMO1在K136位点的修饰。数据集具有明确的生物医学应用背景，可能为哮喘治疗提供新靶点，涵盖生物化学、免疫学等多学科领域。