Thymidine induces macrophage M1 polarization in radiation-induced-lung-injury by ATF3/p38 pathway

Radiation-induced lung injury (RILI) arises as a critical complication of thoracic radiotherapy, characterized by unresolved inflammation and macrophage-driven alveolar damage. While metabolic dysregulation post-radiation is implicated in macrophage polarization, the precise immunometabolic triggers remain undefined. Here, we uncover thymidine-a radiation-elevated metabolite released by injured lung epithelia-as an important regulator of M1 macrophage polarization through multi-omics dissection. Critically, thymidine dietary restriction or AAV9 (Adeno-associated Virus, AAV)-delivered ATF3 in murine models reversed this pathogenic loop, reducing M1 polarization and attenuating pneumonitis. Transcriptomic profiling of irradiated macrophages exposed to thymidine revealed ATF3 suppression and MAPK hyperactivation, establishing a feedforward ATF3/p38 axis that induces epithelial injury. ATF3 overexpression or pharmacological p38 inhibition (SB203580) reversed thymidine's pro-inflammatory reprogramming in vitro. These findings position the thymidine-ATF3/p38 circuit as a lynchpin of radiation-associated immunopathology and advocate metabolic or transcriptional intervention as a viable adjunct to conventional radioprotection strategies.