Linarin 通过 ALDH2 调节保护哮喘诱导的气道上皮铁死亡和炎症
2025/10/31
摘要
背景：哮喘是一种复杂疾病，以气道上皮功能障碍和慢性炎症为特征，持续带来治疗挑战。本研究旨在调查木犀草素-7-O-β-D-芸香糖苷（linarin）在哮喘中的治疗效果，并阐明其潜在的分子机制，重点关注其与醛脱氢酶2（ALDH2）的相互作用。该研究结合了屋尘螨（HDM）诱导的小鼠哮喘模型、多组学生物信息学分析以及一系列体外分子验证实验来评估linarin的效果。
方法：使用HDM诱导的小鼠模型评估linarin的体内疗效。采用多组学和机器学习方法识别linarin的分子靶点。在人气道上皮细胞中进行了一系列体外分子实验，包括细胞热位移分析（CETSA）、下拉实验和免疫荧光，以验证靶点并解析信号级联。
结果：发现linarin直接结合并稳定ALDH2。这种相互作用触发了一个新的ALDH2/MAOA轴，其中稳定的ALDH2下调单胺氧化酶A（MAOA）的表达。调节该轴抑制过度的线粒体分裂并减少氧化应激，从而维持线粒体稳态。线粒体完整性的保持阻止了线粒体DNA（mtDNA）泄漏到细胞质中，进而抑制了环GMP-AMP合成酶-干扰素基因刺激因子（cGAS-STING）炎症通路的激活。同时，该机制通过恢复关键调控蛋白如GPX4来抑制上皮细胞铁死亡。
结论：我们的发现揭示了一个分子机制，其中linarin通过调节ALDH2/MAOA轴，协同抑制三个关键病理过程：线粒体功能障碍、炎症和铁死亡。这项研究为开发linarin作为哮喘的精准靶向治疗药物提供了坚实的理论基础。
Linarin protects against asthma-induced airway epithelial ferroptosis and inflammation via ALDH2 regulation
N. Ding, Q. Bai, H. Jiang, Z. Wang, F. Shang, R. Feng, et al
Abstract
BACKGROUND:
Asthma, a complex disease characterized by airway epithelial dysfunction and chronic inflammation, poses ongoing therapeutic challenges. This study aimed to investigate the therapeutic effects of linarin (acacetin-7-O-β D-rutinoside), a flavone glycoside, in asthma and to elucidate its underlying molecular mechanism, focusing on its interaction with aldehyde dehydrogenase 2 (ALDH2). The study combined a house dust mite (HDM)-induced murine asthma model, multi-omics bioinformatic analysis, and a series of in vitro molecular validation experiments to assess the effects of linarin.
METHODS:
An HDM-induced murine model was used to evaluate linarin’s in vivo efficacy. Multi-omics and ma chine learning approaches were employed to identify linarin’s molecular target. A suite of in vitro molecular assays, including Cellular Thermal Shift Assay (CETSA), pull-down assays, and immunofluorescence, were conducted in human bronchial epithelial cells to validate the target and dissect the signaling cascade.
RESULTS:
Linarin was found to directly bind to and stabilize ALDH2. This interaction triggers a novel ALDH2/MAOA axis, where stabilized ALDH2 downregulates the expression of monoamine oxidase A (MAOA). Regulating this axis inhibits excessive mitochondrial fission and reduces oxidative stress, thereby maintaining mitochondrial homeostasis. The preservation of mitochondrial integrity prevents mitochondrial DNA (mtDNA) leakage into the cytoplasm, which in turn suppresses the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) inflammatory pathway. Simultaneously, this mechanism inhibits epithelial cell ferroptosis by restoring key regulatory proteins like GPX4.
CONCLUSION:
Our findings reveal a molecular mechanism where linarin, by modulating the ALDH2/MAOA axis, coordinately suppresses three key pathological processes: mitochondrial dysfunction, inflammation, and ferroptosis. This study provides a solid theoretical foundation for developing linarin as a precision-targeted therapeutic drug for asthma.
背景：哮喘是一种复杂疾病，以气道上皮功能障碍和慢性炎症为特征，持续带来治疗挑战。本研究旨在调查木犀草素-7-O-β-D-芸香糖苷（linarin）在哮喘中的治疗效果，并阐明其潜在的分子机制，重点关注其与醛脱氢酶2（ALDH2）的相互作用。该研究结合了屋尘螨（HDM）诱导的小鼠哮喘模型、多组学生物信息学分析以及一系列体外分子验证实验来评估linarin的效果。
方法：使用HDM诱导的小鼠模型评估linarin的体内疗效。采用多组学和机器学习方法识别linarin的分子靶点。在人气道上皮细胞中进行了一系列体外分子实验，包括细胞热位移分析（CETSA）、下拉实验和免疫荧光，以验证靶点并解析信号级联。
结果：发现linarin直接结合并稳定ALDH2。这种相互作用触发了一个新的ALDH2/MAOA轴，其中稳定的ALDH2下调单胺氧化酶A（MAOA）的表达。调节该轴抑制过度的线粒体分裂并减少氧化应激，从而维持线粒体稳态。线粒体完整性的保持阻止了线粒体DNA（mtDNA）泄漏到细胞质中，进而抑制了环GMP-AMP合成酶-干扰素基因刺激因子（cGAS-STING）炎症通路的激活。同时，该机制通过恢复关键调控蛋白如GPX4来抑制上皮细胞铁死亡。
结论：我们的发现揭示了一个分子机制，其中linarin通过调节ALDH2/MAOA轴，协同抑制三个关键病理过程：线粒体功能障碍、炎症和铁死亡。这项研究为开发linarin作为哮喘的精准靶向治疗药物提供了坚实的理论基础。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Phytomedicine 2025 Vol. 148 Pages 157398 DOI: 10.1016/j.phymed.2025.157398）
（Phytomedicine 2025 Vol. 148 Pages 157398 DOI: 10.1016/j.phymed.2025.157398）
Linarin protects against asthma-induced airway epithelial ferroptosis and inflammation via ALDH2 regulation
N. Ding, Q. Bai, H. Jiang, Z. Wang, F. Shang, R. Feng, et al
Abstract
BACKGROUND:
Asthma, a complex disease characterized by airway epithelial dysfunction and chronic inflammation, poses ongoing therapeutic challenges. This study aimed to investigate the therapeutic effects of linarin (acacetin-7-O-β D-rutinoside), a flavone glycoside, in asthma and to elucidate its underlying molecular mechanism, focusing on its interaction with aldehyde dehydrogenase 2 (ALDH2). The study combined a house dust mite (HDM)-induced murine asthma model, multi-omics bioinformatic analysis, and a series of in vitro molecular validation experiments to assess the effects of linarin.
METHODS:
An HDM-induced murine model was used to evaluate linarin’s in vivo efficacy. Multi-omics and ma chine learning approaches were employed to identify linarin’s molecular target. A suite of in vitro molecular assays, including Cellular Thermal Shift Assay (CETSA), pull-down assays, and immunofluorescence, were conducted in human bronchial epithelial cells to validate the target and dissect the signaling cascade.
RESULTS:
Linarin was found to directly bind to and stabilize ALDH2. This interaction triggers a novel ALDH2/MAOA axis, where stabilized ALDH2 downregulates the expression of monoamine oxidase A (MAOA). Regulating this axis inhibits excessive mitochondrial fission and reduces oxidative stress, thereby maintaining mitochondrial homeostasis. The preservation of mitochondrial integrity prevents mitochondrial DNA (mtDNA) leakage into the cytoplasm, which in turn suppresses the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) inflammatory pathway. Simultaneously, this mechanism inhibits epithelial cell ferroptosis by restoring key regulatory proteins like GPX4.
CONCLUSION:
Our findings reveal a molecular mechanism where linarin, by modulating the ALDH2/MAOA axis, coordinately suppresses three key pathological processes: mitochondrial dysfunction, inflammation, and ferroptosis. This study provides a solid theoretical foundation for developing linarin as a precision-targeted therapeutic drug for asthma.
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调节性T细胞中p300依赖性调节在过敏性哮喘中起关键作用
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