The Role of OTUD3 as a Novel Oncogenic Driver and Therapeutic Target in Hepatocellular Carcinoma.

INTRODUCTION: Hepatocellular Carcinoma (HCC) represents a significant health challenge globally, characterized by its high incidence and mortality rates. The exact relationship between ovarian-tumor-domain-containing deubiquitinase 3 (OTUD3) expression and HCC remains inadequately explored, presenting a significant gap in our understanding. METHODS: This study employed a comprehensive multi-omics approach, integrating expression analysis and functional validation to elucidate the biological roles of OTUD3 in HCC. RESULTS: OTUD3 exerted tumor-promoting effects in HCC. Analysis of TCGA data revealed significant OTUD3 overexpression in HCC. OTUD3 drove HCC cell cycle progression by promoting the G1/S transition through interaction with and deubiquitination of minichromosome maintenance complex component 7 (MCM7). In vitro, OTUD3 knockdown suppressed HCC proliferation and migration. In vivo, OTUD3 promoted HCC progression in a Diethylnitrosamine (DEN)-induced mouse model. DISCUSSION: These findings establish OTUD3 as a multifunctional oncoprotein driving HCC progression primarily through tumor-intrinsic mechanisms. Its expression in tumor-infiltrating immune cells also suggests a potential role in the immune microenvironment. CONCLUSION: These findings establish the OTUD3-MCM7 axis as a mechanistic link in HCC cell cycle dysregulation and suggest that targeting this interaction may offer a therapeutic strategy.