WDHD1 promotes hepatocellular carcinoma progression by affecting the cell cycle and immune evasion.

WD repeat and HMG-box DNA binding protein 1 (WDHD1) is dysregulated in various tumors; however, its role in hepatocellular carcinoma (HCC) remains unexplored. Herein, we observed that WDHD1 was significantly upregulated in HCC tissues and cell lines and correlated with poor prognosis. Regulatory analysis identified hsa-miR-22, hsa-miR-139, and the transcription factors EP300 and CREBBP as potential modulators of WDHD1. Functional assays revealed that WDHD1 knockdown suppressed cell proliferation, migration, and invasion, whereas its overexpression enhanced these oncogenic phenotypes both in vitro and in vivo. Furthermore, WDHD1 depletion promoted cellular apoptosis. Mechanistically, WDHD1 interacted with components of the CDC45-MCM-GINS (CMG) complex and maintained their structural integrity, thereby facilitating cell cycle progression. Drug sensitivity analysis indicated that elevated WDHD1 expression enhanced responsiveness to cell cycle-targeting agents. Additionally, high WDHD1 levels were associated with increased CD4 memory T cell infiltration, elevated tumor mutational burden (TMB), and enhanced expression of key immune checkpoint markers, suggesting a potential for improved response to immunotherapy in these patients. These findings suggest WDHD1 as a novel oncogenic driver and promising therapeutic target in HCC.