Abstract Radiotherapy resistance remains a major obstacle in nasopharyngeal carcinoma (NPC). This study delineates the role of protein phosphatase 2 regulatory subunit B gamma (PPP2R2C) in NPC radioresistance and its underlying mechanism to identify therapeutic targets. Through integrated bioinformatic analysis, PPP2R2C was identified as a candidate radioresistance driver. In vitro and in vivo functional assays demonstrated that PPP2R2C depletion significantly impaired NPC cell proliferation, migration, and radioresistance, while its overexpression enhanced these phenotypes. Mechanistic investigations revealed PPP2R2C inhibits radiation-induced ferroptosis, evidenced by transmission electron microscopy (TEM), lipid reactive oxygen species (ROS) quantification, malondialdehyde (MDA) assays, and immunoblotting of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Crucially, immunoprecipitation-mass spectrometry (IP-MS), co-immunoprecipitation (Co-IP), and immunofluorescence (IF) confirmed PPP2R2C physically interacts with RPS27L. Further analysis via qPCR, Western blotting, cycloheximide chase, and proteasome inhibition showed PPP2R2C stabilizes RPS27L protein by blocking proteasomal degradation. RPS27L knockdown reversed PPP2R2C-mediated radioresistance and ferroptosis suppression. Clinically, high PPP2R2C expression correlated with poor patient survival. These findings establish that PPP2R2C promotes NPC radioresistance by stabilizing RPS27L to inhibit ferroptosis, positioning the PPP2R2C–RPS27L axis as a novel prognostic biomarker and therapeutic target for overcoming radioresistance.
Fang et al. (Mon,) studied this question.