KLHDC4 serves as a novel prognostic biomarker and drives tumor progression via PI3K/AKT signaling in clear cell renal cell carcinoma.

The clinical significance and molecular mechanisms of KLHDC4 in malignancies, particularly in clear cell renal cell carcinoma (ccRCC), remain poorly understood. In this study, we integrated multi-omics data-including transcriptomic, proteomic, and single-cell RNA sequencing-to systematically evaluate the clinical relevance and functional role of KLHDC4, followed by experimental validation. Our results demonstrated that KLHDC4 is significantly upregulated in multiple cancer types and serves as an independent prognostic biomarker for poor survival in ccRCC. KLHDC4 expression was correlated with immune cell infiltration, tumor mutational profiles, and immune checkpoint expression. Furthermore, KLHDC4 levels predicted response to drug therapies, including immunotherapy and tyrosine kinase inhibitors. Functional experiments showed that KLHDC4 knockdown suppressed proliferation, migration, and invasion in vitro, as well as tumor growth in vivo, whereas its overexpression promoted malignant phenotypes. Mechanistic investigations through RNA sequencing and Western blot analysis indicated that KLHDC4 activates the PI3K/AKT signaling pathway. Rescue assays confirmed that KLHDC4-driven oncogenic effects are partially mediated through this axis. Additionally, molecular docking identified ledipasvir as a potential KLHDC4 inhibitor. Collectively, our findings establish KLHDC4 as a novel prognostic biomarker and therapeutic predictor, highlighting the KLHDC4/PI3K/AKT axis as a potential target for ccRCC treatment.