Global proteomics indicates subcellular-specific anti-ferroptotic responses to ionizing radiation

Cells have many protective mechanisms against background levels of ionizing radiation (IR) orchestrated by molecular changes in expression, post-translation modifications and subcellular localization. Radiotherapeutic treatment in oncology attempts to overwhelm such mechanisms, but radio-resistance is an ongoing challenge. Here, global subcellular proteomics combined with Bayesian modelling 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 radio-resistance mechanisms. These observations were independent of expression changes, emphasizing the utility of global subcellular proteomics and the promising prospect of ferroptosis-inducing therapies for combatting radioresistance.