Background <p>Glioma is the most common primary brain tumor in adults, malignant progression and recurrence are inevitable. Although mechanisms of glioma development and progression have been demonstrated, the underlying driver pathway activation and the related therapeutic targets of recurrent gliomas, notably recurrent isocitrate dehydrogenase (IDH) wild-type gliomas, are rudimentary.</p> Methods <p>We analyzed the differential expression genes (DEGs) between two subgroups of 80 IDH wild-type recurrent gliomas from the Chinese Glioma Genome Atlas (CGGA). We then constructed and validated an 11-gene signature based on cell cycle-related DEGs. SPSS and R languages ​​were used for statistical analysis and graphical work.</p> Results <p>We proposed a molecular classification based on gene expression profiles and divided them into two subtypes that differed in their biological features and prognoses. We then constructed and validated an 11-gene signature based on cell cycle-related DEGs to better explore the association between cell cycle and tumor malignant progression. Additionally, the risk score could predict the sensitivity of patients to radiotherapy or chemotherapy. Functional analysis demonstrated that genes associated with the high-risk group were involved in various aspects of glioma cell cycle regulation. Moreover, the knockdown of <i>SYCE2</i> blocked cell proliferation and improved cell sensitivity to temozolomide (TMZ).</p> Conclusion <p>This study developed a cell cycle-related signature for predicting the prognosis of recurrent IDH wild-type glioma, and identified a novel biomarker <i>SYCE2</i>, which could be used to assess the response of patients to TMZ.</p>