CircRAD23B-208aa Promotes Gastric Cancer Progression by Activating the Unfolded Protein Response through PDIA5...

Gastric cancer (GC) remains a lethal malignancy with limited therapeutic options and poor prognosis. In this study, we employed integrated RNA sequencing and ribosome nascent-chain complex sequencing analyses to identify a coding circular RNA (circRNA), circRAD23B, which is markedly up-regulated in GC tissues. Its expression correlates strongly with advanced tumor stage, lymph node metastasis, and reduced overall survival. We further demonstrate that the splicing factor U2AF65 facilitates circRAD23B biogenesis through direct binding to intron 1 of the RAD23B pre-mRNA. Functionally, circRAD23B encodes a novel 208-amino acid protein via an internal ribosome entry site-dependent mechanism. This protein promotes GC proliferation, invasion, and lung metastasis in vivo. Mechanistically, circRAD23B-208aa recruits the E2 ligase UBC9 to catalyze SUMOylation of PDIA5 at lysine 25, thereby attenuating its ubiquitination and enhancing protein stability. Stabilized PDIA5 facilitates ATF6 activation by promoting its proteolytic processing, nuclear translocation, and transcriptional induction of key unfolded protein response (UPR) effectors-TXNRD1 and HERPUD1-thereby alleviating endoplasmic reticulum stress and promoting tumor survival. Our findings reveal circRAD23B-208aa as the first circRNA-encoded activator of the UPR pathway via posttranslational regulation of PDIA5, highlighting the therapeutic potential of targeting the SUMOylation-dependent PDIA5/ATF6 axis in GC.