The Effect of Metformin on Radiation-Induced Lung Fibrosis in Mice

<b>Introduction:</b> Radiation-induced lung fibrosis (RILF) is a common complication of thoracic radiotherapy. Metformin has been suggested to have a radioprotective effect. <b>Objective:</b> This study explored the radioprotective effects of metformin on RILF and its mechanisms. <b>Methods:</b> C57BL/6J mice were randomly divided into control, ionizing radiation (IR), low-dose metformin (L-Met), and high-dose metformin (H-Met) groups. The IR, L-Met, and H-Met groups received 15 Gy chest irradiation. The L-Met and H-Met groups were administrated 100 or 200 mg/kg metformin from 3 days before irradiation and continued for 6 months. The mice were then sacrificed, and samples were collected for further analysis. <b>Results:</b> RILF was induced in the irradiated mice. Metformin improved lung pathology, inhibited collagen deposition, and reduced inflammatory factors such as high mobility group box 1 (HMGB1), interleukin-1 beta, interleukin-6, tumor necrosis factor alpha in lung tissue, lavage fluid, and serum. Western blot and quantitative real-time PCR analyses revealed that metformin downregulated HMGB1, toll-like receptor 4 (TLR4), and nuclear factor kappaB (NF-κB) expression. Additionally, metformin reversed the irradiation-induced reduction in the abundance of Lactobacillus and Lachnospiraceae at the genus level. Conclusion: Our findings indicated that metformin ameliorates RILF by downregulating the inflammatory-related HMGB1/TLR4/NF-κB pathway and improving intestinal flora disorder.