The Protective Effects and Material Basis of Astragalus membranaceus in the Prevention and Treatment of Radiation-Induced Lung Injury via Modulation of the Keap1-Nrf2 Signaling Pathway.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Astragalus membranaceus (AM), first documented in "Shennong Bencao Jing" is used in Traditional Chinese Medicine (TCM) to tonify lung qi. Radiation-induced lung injury (RILI), a serious complication of thoracic radiotherapy, lacks effective treatment options, highlighting the need to explore AM's therapeutic potential and material basis against RILI. AIM OF THE STUDY: This study aimed to systematically investigate the protective effects of AM against RILI, identify its material basis, and elucidate the underlying mechanisms. MATERIALS AND METHODS: Male C57BL/6 mice received a single 15 Gy whole-thorax X-ray irradiation to establish an RILI model. The protective effect of AM on RILI was assessed via pulmonary function tests, lung index measurement, hematoxylin and eosin (HE) staining, Masson's trichrome staining, and microcomputed tomography (micro-CT) of the mouse lungs. Inflammatory and fibrotic markers were determined using enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), Western blotting (WB), and reverse transcription quantitative polymerase chain reaction (RT-qPCR). To explore the mechanism, nuclear factor erythroid 2-related factor 2 (Nrf2) and the expression of its downstream antioxidant proteins were assessed using immunofluorescence (IF), WB, and RT-qPCR. The metabolic components of AM in lung tissue were detected by UHPLC-Q-Exactive Orbitrap MS. Molecular docking and molecular dynamics (MD) simulations predicted bioactive candidates, which were then validated in cellular assays. RESULTS: AM treatment significantly ameliorated RILI, as evidenced by improved lung function, reduced lung index, and attenuated histological injury, inflammation, and fibrosis. Mechanistically, AM activates Nrf2 and upregulated the expression of its downstream antioxidant proteins, including heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). Metabolomic analysis identified 86 AM-related components in lung tissue. Computational screening and MD simulations demonstrated that Formononetin (FMNT) exhibits a stable binding affinity for Keap1 protein. Cell experiments confirmed that FMNT exerts a significant anti-inflammatory effect, which can be reversed by Nrf2 inhibitors. CONCLUSION: AM protects against RILI by activating the Nrf2 signaling pathway to alleviate oxidative stress and inflammation. FMNT is likely the active component underlying its therapeutic effects. This study provides a scientific basis for the traditional use of AM in lung disorders.

Key Findings

• Astragalus membranaceus (AM) treatment significantly ameliorated radiation-induced lung injury (RILI) by improving lung function and reducing inflammation and fibrosis.
• AM activates the Keap1-Nrf2 signaling pathway, leading to upregulation of downstream antioxidant proteins such as HO-1 and NQO1.
• Metabolomic analysis identified multiple bioactive components of AM in lung tissue, and molecular docking along with cellular assays validated their potential therapeutic roles.

Clinical Significance

Citation

Yao Juan, Wang Huiqin, Zheng Zhiboet al.. The Protective Effects and Material Basis of Astragalus membranaceus in the Prevention and Treatment of Radiation-Induced Lung Injury via Modulation of the Keap1-Nrf2 Signaling Pathway. Journal of ethnopharmacology. 2026-Apr-24.