Targeting ActivatorProtein-1 TranscriptionFactor Subunit FOSL1-Mediated Cuproptosis Sensitizes RadioresistantNon-Small Cell Lung Cancer

Abstract Radiotherapy plays a pivotal role in the management of nonsmall-cell lung cancer (NSCLC), particularly for patients who are not candidates for surgical intervention. Despite its significance, the issue of radioresistance remains a substantial challenge in the treatment of the NSCLC. Therefore, it is crucial to uncover new targets to enhance radiotherapy and investigate the mechanisms underlying radioresistance. Cuproptosis, as an emerging form of cell death dependent on intracellular copper (Cu) ions, remains unclear in its role in radioresistant NSCLCs. This study investigates the development of radioresistant NSCLC models, focusing on the role of the FOS-like antigen 1 (FOSL1) as a significant factor in mediating radioresistance. The FOSL1 gene is downregulated in radioresistant cells. Overexpression of FOSL1 induces mitochondrial damage and dysfunction, causing cuproptosis in radioresistant cells. To tackle the challenge of radioresistance in NSCLC, we propose an innovative nanostrategy focused on cuproptosis, aiming to enhance the efficacy of radiotherapy specifically in radioresistant NSCLC. This intervention could significantly enhance an increase in intracellular Cu2+ concentration and glutathione depletion while also increasing irradiation (IR)-induced oxidative stress and mitochondrial damage. The resulting mitochondrial dysfunction leads to tricarboxylic acid cycle disruption and Fe–S cluster protein destabilization. These cumulative effects ultimately induced cuproptosis and enhanced the response of radioresistant NSCLC cells to IR. Our findings highlight the potential of combining cuproptosis targeting with nanotechnology to enhance the efficacy of radiotherapy, presenting a promising strategy to address radioresistance in clinical contexts.