Global Proteomics Indicates Subcellular-Specific Anti-Ferroptotic Responses to Ionizing Radiation

Cells have many protective mechanisms against background levels of ionizing radiation orchestrated by molecular changes in expression, post-translational modifications, and subcellular localization. Radiotherapeutic treatment in oncology attempts to overwhelm such mechanisms, but radioresistance is an ongoing challenge. Here, global subcellular proteomics combined with Bayesian modeling identified 544 differentially localized proteins in A549 cells upon 6 Gy X-ray exposure, revealing subcellular-specific changes of proteins involved in ferroptosis, an iron-dependent cell death, suggestive of potential radioresistance mechanisms. These observations were independent of expression changes, emphasizing the utility of global subcellular proteomics and the promising prospect of ferroptosis-inducing therapies for combating radioresistance.