A novel protein encoded by circTUBGCP3 blocks ferroptosis and promotes gastric cancer progression.

Circular RNAs play significant roles in the development and progression of various cancers through diverse mechanisms, including the translation of novel proteins. Ferroptosis, a recently identified form of cell death, is associated with tumorigenesis in several cancers; however, its pathological mechanisms in gastric cancer (GC) remain unclear. Here, we found that circTUBGCP3 expression was elevated in GC tissues compared with normal gastric tissues. Moreover, circTUBGCP3 can be translated into a previously undescribed protein, TUBGCP3-230aa. In vitro and in vivo functional analyses demonstrated that both circTUBGCP3 and TUBGCP3-230aa promote rapid GC cell proliferation, with TUBGCP3-230aa exerting independent biological effects. Enolase 1 (ENO1), a glycolytic enzyme, was identified as an interacting partner of TUBGCP3-230aa, leading to activation of the glycolytic pathway and inhibition of ferroptosis in GC cells in vitro and in vivo. Mechanistically, TUBGCP3-230aa stabilizes ENO1 through posttranslational regulation, thereby repressing ferroptosis. Together, our results identify circTUBGCP3 and TUBGCP3-230aa as potential biomarkers for GC and uncover a novel mechanism of ferroptosis regulation, which may represent a promising therapeutic target. Furthermore, our findings highlight a critical moonlighting function of ENO1 in GC and underscore its potential as a novel target for cancer therapy.