Chronic obstructive pulmonary disease (COPD) continues to be a significant public health concern and an ongoing challenge for clinicians in the 21st century (Lopez-Campos et al., 2016). The repeated damage-repair process of the airway wall constitutes a primary pathological basis for airflow limitation in COPD(Zi et al., 2023). The prevalence of excessive central airway collapse (ECAC) is 35 % in patients with stable COPD and 39 % in patients with AECOPD(Leong et al., 2017). Airway narrowing or collapse due to COPD can impede airflow, thereby worsening dyspnea and increasing the risk of exacerbations (Glynos et al., 2015). Therefore, it is crucial to explore therapeutic strategies to effectively alleviate COPD.

Cigarette smoke exposure (CSE) causes airway damage primarily through inflammatory responses, oxidative stress, and metabolic disruptions (Che et al., 2020; Wang et al., 2018). Numerous studies have demonstrated the involvement of multiple inflammatory cell types, such as macrophages, neutrophils, and T cells, in the pathophysiology of COPD(Barnes, 2014, 2016; Guo et al., 2022). These cells release a variety of mediators, such as tumor necrosis factor (TNF)-α, reactive oxygen species (ROS), interleukin (IL)-8 (Barnes, 2013), and their sustained release leads to airway epithelial damage and lung parenchyma destruction. Signaling pathways such as JAK-STAT regulate the expression of inflammation-related genes (Banerjee et al., 2017; Montero et al., 2021), and this pathway can influence both anti- and pro-inflammatory cytokine levels (Nicholson et al., 2016; Zhao et al., 2020). The upregulation of STAT1 and STAT3 in the lung tissues of smokers and patients with severe COPD, compared to nonsmokers, is associated with activation of the JAK-STAT1/3 pathway (Yew-Booth et al., 2015). This persistent activation sustains the inflammatory cascade within the airways, exacerbating tissue damage and compromising repair processes. On the other hand, pulmonary oxidative stress in COPD patients arises from both exogenous cigarette smoke oxidants and endogenous ROS generated by lung cells (Barnes et al., 2019; Hwang et al., 2011). Excess ROS can directly damage airway epithelial cells and lung parenchyma, and activate cytokines, which in turn trigger the inflammatory response and exacerbates COPD airway damage (Zi et al., 2023). Glutathione (GSH) is an important endogenous antioxidant, which exerts its antioxidant effects by interacting directly with ROS or acting as a factor for enzymes to protect cells from oxidative damage. Studies have shown that glutathione peroxidase (GPx) activity is significantly reduced in COPD patients, and glutathione reductase (GR) activity is also diminished. This impairment disrupts the glutathione cycle, weakens antioxidant defenses, and leaves the airway epithelium highly susceptible to oxidative damage, which accelerates COPD progression (Lavrentiadou et al., 2001).

Evidence has shown that traditional Chinese medicine can significantly alleviate symptoms in patients with COPD, reduce the frequency of acute exacerbations, and improve patients' quality of life (Ren et al., 2020; Zhang et al., 2021). Danggui Buxue Decoction (DBD) is a traditional Chinese herbal formula and was first recorded in “Nei Wai Shang Bian Huo Lun” by Li Dongyuan over 700 years ago (Zhou et al., 2025). It is a famous formula for supplementing Qi and blood (Yang et al., 2025). The formula of DBD is formulated with a 5:1 mass ratio of Astragalus mongholicus Bunge to Angelica sinensis (Oliv.) Diels (Hua et al., 2019), and the above plant names have been checked against http://mpns.kew.org (June 26th, 2025). According to TCM theory, the lung is intimately associated with respiratory function and regarded as the organ that governs Qi and breathing (He et al., 2025). Deficiency of lung Qi directly leads to general Qi deficiency, which in turn results in a deficiency of both Qi and blood. Consequently, DBD, a classic formula for tonifying Qi and nourishing blood, is well-suited for addressing pulmonary disorders. It is currently used in clinical practice to treat lung cancer. Clinical studies have demonstrated its significant efficacy as an adjunctive therapy. For instance, in managing leukopenia following radiotherapy for lung cancer, the modified DBD achieved a markedly high response rate of 97.62 %, which was significantly superior to the control group's rate of 81.40 %, and was further shown to enhance lymphocyte subset levels (Chen et al., 2023; Du et al., 2009). Furthermore, when combined with western medicine, modified DBD increased the overall response rate for postpartum fever to 97.96 % and significantly shortened the duration of fever (Leng, 2019). Pharmacological investigations have revealed that the mechanism of DBD against pulmonary inflammation and fibrosis in an IPF rat model involves the suppression of the TLR4/NLRP3 pathway (Wang et al., 2021). Moreover, it can inhibit pulmonary fibrosis by down-regulating the expression of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) (Zhang et al., 2022). Nevertheless, research on pulmonary diseases has been largely confined to pulmonary fibrosis, and the therapeutic potential of DBD in COPD remains to be elucidated.

The airway of Drosophila melanogaster exhibits pathological features highly similar to those in human airway disease. Upon stimulation by smoke or pathogens, it mounts a physiological response highly consistent with that observed in human (Ehrhardt et al., 2022; Gavrilchenko et al., 2024; Wagner et al., 2021). This model allows for the observation of the overall effects of drugs, making it a suitable model for evaluating the efficacy of herbal compounds and their active constituents (Hua et al., 2016). In addition, the rat model can be used to recapitulate key structural and functional impairments of COPD, including alterations in lung function, inflammatory responses, and histological changes (Ma et al., 2025). The rat model can more realistically reflect the pathophysiological process of human COPD(Wang et al., 2025). Therefore, the combination of Drosophila melanogaster and rats allows for the rapid screening of effective drugs and elucidation of the molecular mechanisms that mitigate airway damage.

This study demonstrated that DBD could alleviate COPD tracheal injury by regulating JAK-STAT pathway and glutathione metabolism in Drosophila melanogaster and rat COPD models. Subsequently, four core active components of DBD were found to alleviate CS-induced tracheal injury. These results provide an experimental foundation for the research and clinical application of Chinese medicinal preparations, and provide new impetus for the development of the respiratory system field.