Folic Acid Protects Against Radiation‐Induced Lung Injury by Suppressing Senescence of Lung Epithelial Cells

Radiation-induced lung injury (RILI) is a prevalent complication of thoracic tumor radiotherapy, severely compromising treatment efficacy and the patients' quality of life, yet effective prevention or treatment strategies remain elusive. Folic acid (FA), a water-soluble vitamin, plays critical roles in DNA synthesis/repair, cell cycle regulation, epigenetic regulation via methylation, oxidative stress response, and embryonic development. However, its radioprotective role has not been systematically elucidated. This study aimed to investigate its effects and molecular mechanisms during RILI. The RILI murine model showed that folic acid supplementation significantly alleviated radiation-induced lung tissue damage, body weight loss, and inflammatory cell infiltration. Meanwhile, folic acid mitigated radiation-induced DNA damage and cellular senescence in lung tissues and lung epithelial cell lines. RNA sequencing identified a 29-gene SASP signature (including CCL5, CXCL2, CXCL10), which was significantly suppressed by folic acid in irradiated lungs. Moreover, folic acid inhibited SASP production by suppressing the phosphorylation of P38 MAPK/NF-κB signaling pathway. By integrating in vivo and in vitro models, we revealed that folic acid exerts its radioprotective effects by reducing cellular senescence and the production of SASP. Taken together, these findings indicated that folic acid is potentially a novel therapeutic strategy for RILI.