CYP4A22-AS1 controls YBX1 nuclear accumulation to promote metabolic adaptation and radioresistance in cervical adenocarcinoma

Cervical adenocarcinoma exhibits intrinsic resistance to radiotherapy, yet the molecular mechanisms underlying this phenotype remain poorly understood. We integrated transcriptomic analyses of TCGA and an independent RNA-sequencing cohort to identify dysregulated long noncoding RNAs (lncRNAs) in cervical adenocarcinoma. Multiple functional studies, including clonogenic survival, proliferation, apoptosis, glycolytic flux, xenograft irradiation, patient-derived organoids, and clinical validation, were combined with RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, immunofluorescence, and rescue experiments to define the underlying molecular mechanism. CYP4A22-AS1 emerged as a consistently upregulated lncRNA in cervical adenocarcinoma and was associated with aggressive clinicopathological features and poor clinical outcome. Mechanistically, CYP4A22-AS1 directly interacted with the RNA- and DNA-binding protein YBX1, promoted its nuclear accumulation, and enhanced YBX1 recruitment to the glycolytic enzyme PGK1 promoter, resulting in transcriptional activation of PGK1. Disruption of the CYP4A22-AS1–YBX1–PGK1 axis suppressed glycolytic activity, impaired DNA damage repair, increased radiation-induced apoptosis, and markedly enhanced radiosensitivity in vitro. Consistent with these findings, CYP4A22-AS1 promoted resistance to irradiation in xenograft and patient-derived organoid models. Clinically, elevated CYP4A22-AS1 and PGK1 expression correlated with unfavorable prognosis. Our findings identify a previously unrecognized lncRNA-dependent mechanism in which CYP4A22-AS1 promotes YBX1 nuclear accumulation and PGK1 transactivation, thereby coupling metabolic adaptation to DNA damage repair and intrinsic radioresistance in cervical adenocarcinoma. This pathway represents a potential therapeutic vulnerability for improving radiotherapy response.