Unraveling the temporal dynamics of radiation-induced lung injury: a multi-omics integration of transcriptomic, proteomic, and metabolic reprogramming

Radiation-induced lung injury (RILI) arises from the unavoidable exposure of normal lung tissue during radiotherapy for thoracic malignancies. It remains a dose-limiting complication in thoracic radiotherapy, critically impacting treatment efficacy and long-term patient survival. Despite its clinical significance, the dynamic molecular reprogramming underlying RILI progression remains poorly characterized. Utilizing a C57BL/6J thoracic irradiation mouse model validated by histopathological analysis, we implemented an integrative tri-omics approach (RNA-seq, LC-MS/MS proteomics, and UHPLC-QTOF metabolomics) to systematically map the temporal evolution of RILI at critical phases: acute inflammation, transitional, and fibrotic. The three periods correspond to 4 weeks, 8 weeks, and 16 weeks after the mice received 16 Gy of electron beam irradiation to the thoracic region. Combined analysis using complete-linkage hierarchical clustering revealed co-expression modules, and Ces2e was identified as a pivotal node exhibiting sustained upregulation at both transcriptional and translational levels during early pathogenesis. Functional enrichment revealed time-dependent activation of xenobiotic metabolism and extracellular matrix (ECM)-receptor interaction pathways, with Ces2e overexpression correlating with macrophage polarization and lipid peroxidation accumulation. This temporal multi-omics atlas not only deciphers stage-specific molecular signatures of RILI but also nominates Ces2e as a candidate early-stage molecular marker.