Abstract Background: Cervical adenocarcinoma exhibits poor responsiveness to radiotherapy and inferior survival compared with squamous cell carcinoma. The molecular mechanisms underlying its intrinsic radiation resistance remain largely unknown. Methods: Integrative analysis of TCGA and our RNA-seq cohort identified CYP4A22-AS1 as one of the most upregulated lncRNAs in cervical adenocarcinoma. qRT-PCR confirmed higher CYP4A22-AS1 expression in tumors with short disease-free survival (DFS). RNA pulldown, mass spectrometry, and RIP assays defined YBX1 as a direct CYP4A22-AS1-binding partner. Immunofluorescence and ChIP-qPCR assays examined YBX1 nuclear localization and promoter occupancy of PGK1, respectively. Functional effects of CYP4A22-AS1, YBX1, and PGK1 silencing were assessed by CCK-8, colony, EdU, and TUNEL assays in HeLa and C33A cells, and validated in xenograft models. Results: CYP4A22-AS1 was markedly overexpressed in cervical adenocarcinoma relative to normal cervix. Clinically, high CYP4A22-AS1 and PGK1 levels correlated with shorter DFS. Mechanistically, CYP4A22-AS1 binds YBX1 and enhances its nuclear translocation, thereby promoting YBX1 recruitment to the PGK1 promoter and activating glycolytic metabolism. Knockdown of CYP4A22-AS1 or PGK1 suppressed proliferation and markedly increased radiosensitivity both in vitro and in vivo. Conclusions: This study identifies CYP4A22-AS1 as a novel oncogenic lncRNA that drives radiation resistance through YBX1-mediated PGK1 transactivation. Clinically, CYP4A22-AS1 overexpression predicts poor outcome, while its inhibition restores radiation sensitivity. Targeting the CYP4A22-AS1-YBX1-PGK1 signaling axis offers a promising therapeutic strategy to overcome radioresistance in cervical adenocarcinoma. Citation Format: Mingyi Zhou, Chunlai Li, Cristina Ivan, Simone Anfossi, Linda Fabris, Melanie Winkle, Recep Bayraktar, Meng Chen, Lan Pang, Masayoshi Shimizu, Francois Claret, George Calin, . CYP4A22-AS1-YBX1 axis drives radiation resistance in cervical adenocarcinoma via PGK1 transactivation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1366.
Zhou et al. (Fri,) studied this question.