Unraveling the molecular landscape of chronic radiation injury: From oxidative stress signaling to translational modeling (Review)

The expanding footprint of human radiation exposure, driven by advances in interventional diagnostics, the resurgence of the nuclear industry and the deep‑space exploration, has necessitated a paradigm shift from understanding acute syndromes to the biological effects of chronic, low‑dose‑rate irradiation. Unlike acute injury, chronic radiation injury (CRI) is a distinct biological entity characterized by the progressive accumulation of sublethal damage, niche remodeling and the propagation of the senescence‑associated secretory phenotype, which collectively drive systemic inflammaging. Deciphering these non‑linear dose‑response dynamics requires high‑fidelity animal models that deconstruct mechanisms often obscured by latency in human epidemiological studies. The present review critically synthesizes the methodological evolution of CRI modeling, contrasting continuous external beam paradigms with internal radionuclide contamination systems. The present study aimed to summarize the pathophysiology of multi‑organ exhaustion, specifically detailing the mechanisms of hematopoietic niche senescence, pulmonary fibrosis and stochastic carcinogenesis, and propose a multidimensional validation framework integrating deep phenotyping, digital pathology and circulating biomarkers to establish rigorous construct validity. Finally, the present study aimed to bridge the translational gap by aligning preclinical screening with the Food and Drug Administration Animal Rule‑a regulatory pathway permitting the approval of medical countermeasures based on animal efficacy data when human trials are unethical, advocating a future defined by single‑cell spatial omics and artificial intelligence‑driven precision radioprotection.