AbstractBackgroundDespite great advances in the prevention, diagnosis, treatment, and management regarding hepatocellular carcinoma (HCC), the overall prognosis of HCC remains unfavorable. The expression profile, prognostic role, and biological functions of F‐box‐only protein 43 (FBXO43) in HCC remain unclear. Here, we determine the expression profile and prognostic value of FBXO43 in patients with HCC.Materials and MethodsA total of 467 HCC patients and their clinicopathological data were collected from the Second Affiliated Hospital of Jiaxing University, the Cancer Genome Atlas (TCGA), and Genotype‐Tissue Expression (GTEx) databases. The expression profile, prognostic value, biological functions, and underlying mechanism of its involvement ofFBXO43were explored based on TCGA, Gene Expression Omnibus (GEO), LinkedOmics, and Cancer Dependency Map (DepMap). The expression of FBXO43 in 93 paired liver tissues was investigated via immunohistochemical staining, tissue microarray analysis, and Western blot. The prognostic value was assessed using survival analysis.ResultsFBXO43RNA was upregulated in HCC liver tissues and was associated with an unfavorable prognosis (p< 0.05). Furthermore, FBXO43 protein was overexpressed in HCC liver tissues compared with that in paired normal liver tissues. Overexpression of FBXO43 protein was significantly associated with advanced TNM stage, large tumor size, lymphatic invasion, distant metastasis, earlier cancer recurrence, and decreased overall survival after radical surgery (p< 0.05). Cox regression analysis showed that FBXO43 had significant prognostic value in HCC. Importantly,FBXO43and its co‐expressed genes were mainly involved in cell cycle regulation, DNA replication, metabolic regulation, and so on.FBXO43knockdown could significantly affect the HCC cell lines growth and proliferation.ConclusionsWe first revealed thatFBXO43was overexpressed in liver HCC tissues at the RNA and protein levels and served as an independent prognostic factor for HCC patients. Therefore,FBXO43is worth investigating as a potential HCC treatment target.