Title : Linarin protects against asthma induced airway epithelial ferroptosis and inflammation via ALDH2 regulation
Abstract:
Background: Asthma a complex disease characterized by airway epithelial dysfunction and chronic inflammation, poses ongoing therapeutic challenges.
Aims: 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).
Study Design: 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 HDMinduced murine model was used to evaluate linarin’s in vivo efficacy. Multi-omics and machine 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.
Key words: Linarin; Asthma; ALDH2; cGAS-STING; Ferroptosis; Abbreviations
