Engineering ferroptosis radiosensitizer for SPARC-targeted degradation: A strategy to reverse radioresistant...

Radioresistance poses a significant obstacle in the management of Non-Small Cell Lung Cancer (NSCLC), often diminishing the effectiveness of radiotherapy and leading to treatment failures and adverse clinical outcomes. This study develops radioresistant NSCLC models, revealing that Secreted Protein Acidic and Rich in Cysteine (SPARC) as a crucial modulator of this resistance, through the inhibition of ferroptosis. To address this radioresistance, we propose a novel ferroptosis-oriented radiosensitization strategy specifically designed to enhance radiotherapy effectiveness in radioresistant NSCLC. Our approach utilized engineered radiosensitizers to facilitate enhanced X-ray energy deposition, which significantly amplified radiation-induced lipid peroxidation while specifically targeting and degrading SPARC proteins. This dual mechanism works by elevating PTGS2 levels induced by radiation, thereby intensifying lipid peroxidation, while concurrently inhibiting the upregulation of adaptive ferroptosis-suppressing GPX4 and SLC7A11. Consequently, this strategy effectively reverses the pro-oxidant intracellular environment characteristic of radiotherapy resistance. By promoting ferroptosis and reestablishing cellular sensitivity to radiation, these radiosensitizers significantly enhance the response of cancer cells to radiotherapy. Our findings underscore the potential of integrating ferroptosis targeting with radiosensitization as an efficient strategy to enhance antitumor efficacy of radiotherapy, offering a promising avenue to overcome radioresistance in clinical settings.