Targeting Oxidative and Nitrosative Stress: Mechanistic Insights and Therapeutic Strategies for Radiation-Induced Lung Injury

Abstract

Abstract Radiation-induced lung injury (RILI) remains a major complication of thoracic radiotherapy, limiting curative treatment for thoracic malignancies. Oxidative and nitrosative stress have emerged as central mechanisms driving the initiation and progression of RILI, orchestrating inflammatory signaling, immune dysregulation, and fibrotic remodeling. In this review, we first introduce the “pro-stress milieu” created by the pre-existing tumor microenvironment (TME) briefly. Then we provide a detailed mechanistic dissection of the molecular and cellular pathways through which ionizing radiation generates reactive oxygen and nitrogen species, including water radiolysis, mitochondrial dysfunction, enzyme activation (NOX, DUOX, COX-2, iNOS), and impairment of endogenous antioxidant defenses such as Nrf2 and SOD. We also highlight emerging mechanisms, such as tetrahydrobiopterin (BH4) depletion and NOS uncoupling, which broaden the current understanding of redox imbalance in RILI. Subsequently, we provide a comprehensive overview of therapeutic strategies targeting oxidative and nitrosative stress, spanning small-molecule drugs, natural metabolites, mesenchymal stem cells and exosomes, bioengineered nanomaterials, plant-derived extracts, and traditional medicines. Each modality is assessed for its mechanistic basis, efficacy in preclinical models, and, crucially, the challenges hindering clinical adoption. Finally, we discuss current limitations and future perspectives, including biomarker development, precision redox modulation, and combinatorial approaches, which may accelerate the translation of redox-targeted therapies into effective interventions for RILI.