Molecular mechanisms and network interactions in radiation-induced lung injury

Radiation-induced lung injury (RILI) represents a major dose-limiting complication of thoracic radiotherapy, profoundly affecting therapeutic outcomes and patient quality of life. Although RILI is clinically significant, its molecular underpinnings are not fully elucidated, hampering the development of targeted interventions. This review summarizes the current understanding of the molecular mechanisms underlying RILI, with a focus on radiation-induced DNA damage, oxidative stress, regulated cell death, inflammatory and fibrotic signaling, cellular senescence, and immune microenvironment dysregulation. Particular attention is given to the crosstalk among these processes and their roles in driving maladaptive lung repair. We also discuss recent advances in single-cell and spatial omics that have improved the understanding of cellular heterogeneity and spatiotemporal dynamics in RILI, as well as emerging targeted therapeutic strategies. Synthesizing contemporary molecular and cellular insights, this review constructs an integrative framework for deciphering RILI mechanisms and highlights promising avenues for future research and clinical application.