Glioma is one of the most common malignant tumors and shows a high metastasis rate and poor prognosis. KLHDC8A has been implicated in several cancers, but its role in glioma and its potential as a biomarker remain unclear. We conducted a pan-cancer analysis of KLHDC8A using multiple databases and assessed its expression levels, survival associations, and diagnostic utility. Kaplan–Meier survival analysis and Receiver Operating Characteristic (ROC) curves were utilized to evaluate KLHDC8A’s prognostic and diagnostic potential. Additionally, we investigated KLHDC8A's role in glioma cell proliferation and its involvement in the Wnt/β-catenin signaling pathway. Our pan-cancer analysis revealed significant dysregulation of KLHDC8A across various tumors. Elevated KLHDC8A expression was associated with poor overall survival (OS) in cancers including ACC, KIRP, LGG, and STAD. Disease-specific survival (DSS) analysis indicated worse outcomes in ACC, KIRP, and LGG with high KLHDC8A levels. ROC curve analysis demonstrated KLHDC8A's strong diagnostic potential for glioblastoma multiforme (GBM) and lower-grade gliomas (LGG), with AUC values of 0.920 and 0.748, respectively. In glioma patients, high KLHDC8A expression correlated with shorter OS and DSS in LGG, while no significant correlation was observed in GBM. Multivariate Cox regression confirmed KLHDC8A as an independent prognostic factor for OS and DSS in LGG. Knockdown experiments in glioma cell lines U251 and U87 showed that KLHDC8A silencing led to reduced cell proliferation and colony formation, which was associated with downregulation of key proteins in the Wnt/β-catenin pathway. Overall, KLHDC8A is a promising biomarker for the diagnosis and prognosis of LGG, and its high expression is linked to poor survival outcomes. The gene's involvement in the Wnt/β-catenin signaling pathway underscores its role in glioma progression, highlighting KLHDC8A’s potential as a therapeutic target and diagnostic marker, particularly for LGG.
