Circular RNAs (circRNAs) are RNA transcripts that are widespread in the eukaryotic genome. Recent evidence indicates that circRNAs play important roles in tissue development, gene regulation, and carcinogenesis. However, whether circRNAs encode functional proteins remains elusive, although translation of several circRNAs was recently reported. This study identified circ-FBXW7, a novel circRNA, which encodes a 21-kDa protein named FBXW7-185aa. The study found that FBXW7-185aa inhibits glioma cell proliferation and cell cycle progression, while its knockdown promotes malignant phenotypes in vitro and in vivo. FBXW7-185aa reduces the half-life of c-Myc by antagonizing USP28-induced c-Myc stabilization. Circ-FBXW7 and FBXW7-185aa levels were reduced in glioblastoma clinical samples compared with their paired tumor-adjacent tissues. Circ-FBXW7 expression positively associated with glioblastoma patient overall survival. The study demonstrates that endogenous circRNAs can encode functional proteins in human cells, and circ-FBXW7 and FBXW7-185aa have potential prognostic implications in brain cancer. The findings suggest that circRNAs may have a role in glioma carcinogenesis and patient clinical prognosis. The study was limited to cultured cells and xenograft animal models, and the clinical significance of circ-FBXW7 and FBXW7-185aa may need to be addressed in larger cohorts. The study provides clear evidence that circRNAs can encode functional proteins in vivo.Circular RNAs (circRNAs) are RNA transcripts that are widespread in the eukaryotic genome. Recent evidence indicates that circRNAs play important roles in tissue development, gene regulation, and carcinogenesis. However, whether circRNAs encode functional proteins remains elusive, although translation of several circRNAs was recently reported. This study identified circ-FBXW7, a novel circRNA, which encodes a 21-kDa protein named FBXW7-185aa. The study found that FBXW7-185aa inhibits glioma cell proliferation and cell cycle progression, while its knockdown promotes malignant phenotypes in vitro and in vivo. FBXW7-185aa reduces the half-life of c-Myc by antagonizing USP28-induced c-Myc stabilization. Circ-FBXW7 and FBXW7-185aa levels were reduced in glioblastoma clinical samples compared with their paired tumor-adjacent tissues. Circ-FBXW7 expression positively associated with glioblastoma patient overall survival. The study demonstrates that endogenous circRNAs can encode functional proteins in human cells, and circ-FBXW7 and FBXW7-185aa have potential prognostic implications in brain cancer. The findings suggest that circRNAs may have a role in glioma carcinogenesis and patient clinical prognosis. The study was limited to cultured cells and xenograft animal models, and the clinical significance of circ-FBXW7 and FBXW7-185aa may need to be addressed in larger cohorts. The study provides clear evidence that circRNAs can encode functional proteins in vivo.