Prolactin-Releasing Hormone Receptor (PRLHR) enhances radiosensitivity and exacerbates DNA damage in glioblastoma post-irradiation by inhibiting Y-box-binding protein-1 (YBX1) nuclear translocation: a novel perspective on precision radiotherapy.

Radiotherapy is a cornerstone for glioblastoma multiforme (GBM), yet its efficacy is severely hampered by intrinsic radioresistance, the molecular basis of which remains elusive, and overcoming this resistance poses a persistent challenge for GBM therapeutics. This study aims to identify novel key regulators of radiosensitivity in glioblastoma (GBM), with the goal of developing potent radiosensitizers. By analyzing patient cohorts, we identified prolactin-releasing hormone receptor (PRLHR) as a differentially expressed molecule, with significantly elevated levels in glioma specimens from the long PFS group compared to the short PFS group. This discovery prompted us to investigate PRLHR's role in modulating GBM radiosensitivity and DNA repair. Using in vitro and in vivo models, we found PRLHR overexpression enhanced GBM radiosensitivity by promoting DNA damage accumulation and attenuating repair pathways. Mechanistically, PRLHR interacts with Y-box-binding protein-1 (YBX1), inhibiting its nuclear translocation to reduce nuclear YBX1 levels, thereby compromising DNA repair efficiency. We further demonstrated repressor element-1 binding transcription factor (REST) directly binds the PRLHR promoter to transcriptionally repress its expression. Notably, degradation of REST by the antagonist X5050 upregulated PRLHR, increased DNA damage, and enhanced the therapeutic efficacy of radiotherapy in preclinical models. Our findings delineate PRLHR as a critical regulator of GBM radiosensitivity and establish X5050 as a promising radiosensitizing agent, offering a novel precision strategy to overcome radioresistance.