Natural compound 5,7,8‑trimethoxyflavone mitigates radiation‑induced lung injury by suppressing EMT and PI3K/Akt pathway

Radiation-induced lung injury (RILI) remains a dose-limiting and life-threatening complication of thoracic radiotherapy.The present study aimed to evaluate the therapeutic efficacy and mechanism of the naturally extracted flavonoid, 5,7,8-trimethoxyflavone (HY-N7656), in inhibiting RILI.Lung injury in mice was evaluated using micro-computed tomography, histopathological analysis, enzyme-linked immunosorbent assay and western blotting.Network pharmacology was conducted to predict the potential therapeutic targets and signaling pathways of HY-N7656 in RILI.Cell Counting Kit-8, wound healing, immunofluorescence, reverse transcription-quantitative (RT-q) PCR and protein expression analyses were carried out in vitro using TGF-β-stimulated A549 cells to evaluate epithelial-mesenchymal transition (EMT) and signaling activity.Results of the present study revealed that HY-N7656 markedly alleviated pulmonary inflammation and fibrosis in irradiated mice, leading to a reduction in α-smooth muscle actin expression.In addition, EMT was effectively reversed following treatment with HY-N7656 in A549 alveolar epithelial cells treated with TGF-β, accompanied by restoration of E-cadherin expression and downregulation of mesenchymal markers, such as N-cadherin and vimentin.Network pharmacology analysis and molecular docking validation identified the PI3K/Akt pathway as a central target, which was subsequently confirmed via western blot analysis.Moreover, results of the present study demonstrated that HY-N7656 inhibited radiation-induced activation of PI3K and Akt.To the best of the authors' knowledge, the present study was the first to demonstrate that HY-N7656 modulates the PI3K/Akt signaling pathway to suppress the progression of EMT in RILI, establishing HY-N7656 as a multi-target inhibitor of RILI.These findings present a potential strategy to enhance the safety of radiotherapy, warranting further preclinical and clinical evaluation.