Radiation-induced lung injury (RILI) is a common complication associated with thoracic radiotherapy for malignant tumors such as lung cancer, breast cancer, and esophageal cancer [1]. Its incidence is influenced by factors including radiation dose, irradiated area, fractionation schedule, and individual patient variability [2]. Clinically, RILI manifests with a spectrum of symptoms, ranging from asymptomatic cases to severe pulmonary fibrosis, which can significantly impair respiratory function and even pose life-threatening risks. With the widespread application of radiotherapy in the treatment of various thoracic malignancies, the prevention and management of radiation pneumonitis (RP), which is the early manifestations of RILI have become pivotal areas of clinical research [3]. Current therapeutic modalities for RILI encompass a multifaceted approach, including pharmacological interventions, supportive care, lifestyle and nutritional support, physical therapy, and advanced treatment techniques [4], [5]. Corticosteroids are frequently employed in the management of early-stage RILI, leveraging their anti-inflammatory properties to mitigate lung tissue damage. Antibiotics are utilized to prevent and treat secondary infections. Additionally, antifibrotic agents, antioxidants, and cytokine inhibitors have demonstrated some efficacy in alleviating RILI symptoms. Supportive measures such as oxygen therapy, bronchodilators, and mucolytic agents aid in improving respiratory function and quality of life [1]. However, the existing treatment strategies for RILI are fraught with significant limitations. Corticosteroids demonstrate short-term efficacy but carry long-term risks of immunosuppression and osteoporosis. Antifibrotic agents exhibit limited capacity to reverse established pulmonary fibrosis. Advanced radiotherapy techniques like IMRT/SBRT reduce radiation exposure to normal lung tissue but cannot entirely eliminate RILI risks [6], [7]. Therefore, it is essential to develop safer and more effective strategies for the prevention and treatment of RILI.

The critical role of nucleotide metabolites in modulating inflammation is well-documented across various diseases, underscoring their significance in pathological processes. In gout, uric acid crystals induce joint inflammation via NLRP3 inflammasome activation [8]. Adenosine derivatives mediate endothelial dysfunction through adenosine receptor signaling in atherosclerosis [9]. ATP/adenosine imbalance drives immune dysregulation in rheumatoid arthritis and IBD (Inflammatory bowel diseases, IBD) [10], [11], and GTP fuels malignancy through oncogenic pathways in tumor microenvironments [12]. Macrophages play a pivotal yet paradoxical role in RILI. Early post-irradiation, infiltrating macrophages adopt a pro-inflammatory M1 phenotype, releasing cytokines and reactive oxygen species that exacerbate tissue damage and alveolar edema. Conversely, during later phases, M2-polarized macrophages dominate, promoting fibrosis via TGF-β secretion and collagen deposition [13]. This polarization imbalance critically determines RP progression. Our preliminary non-targeted metabolomics revealed significant thymidine metabolite accumulation in epithelial cells post-radiation [14], suggesting radiation-disrupted nucleotide homeostasis may promote tissue damage through macrophage polarization. Therefore, we hypothesize that radiation-induced accumulation of thymidine metabolite promotes macrophage polarization toward a pro-inflammatory phenotype, thereby contributing to the early progression of RILI.

To validate this hypothesis, we first established an in vitro epithelial cell radiation model to investigate the impact of epithelial cell-derived metabolites, particularly thymidine, on macrophage pro-inflammatory phenotypes. Furthermore, we developed a dietary intervention model and successfully reduced the severity of RILI by restricting thymidine intake prior to thoracic irradiation. Additionally, we found that limiting thymidine intake activated the ATF3/MAPK pathway, inhibiting the polarization of macrophages to a pro-inflammatory phenotype, which may underline the mechanism by which thymidine restriction alleviates RILI.