Stabilization of m6A-Modified PHGDH mRNA by IGF2BP2 Reinforces Serine-Dependent Antioxidant Defense to Induce Cervical Cancer Radioresistance

Radiotherapy is the standard radical therapy for locally advanced cervical cancer, with approximately 80% of patients receiving radiation treatment. Nevertheless, intrinsic or acquired radioresistance reduces therapeutic efficacy. Previous studies have confirmed that mRNA methylation modification, metabolic reprogramming and redox homeostasis are involved in the regulation of radioresistance; however, the specific molecular mechanism underlying radioresistance in cervical cancer remains unclear. We integrated transcriptomic–metabolomic profiling, cell-biological experiments, radiobiological assays, RIP, molecular rescue experiments, xenograft tumor models and clinical specimens to dissect this regulatory axis. We identified IGF2BP2 as a key molecule governing radioresistance in cervical cancer. IGF2BP2 binds to the m6A-modified sites on PHGDH mRNA to maintain its stability and subsequently potentiates serine metabolism. Excessive serine metabolism elevates intracellular GSH and SAM levels, sustains cellular antioxidant homeostasis and confers cellular radioresistance. Data from animal models and clinical specimens further validated this regulatory axis. This study uncovers the m6A-IGF2BP2-PHGDH–serine metabolism–antioxidant regulatory axis, providing promising prognostic biomarkers and a radiosensitizing strategy combining a serine-restricted diet with radiotherapy for cervical cancer.