Advanced hepatocellular carcinoma (HCC) remains one of the main causes of cancer death worldwide and was reported by the Surveillance Epidemiology End Results (SEER) as the ‘fastest increasing cause of cancer-related death’. In Belgium, the number of new diagnoses increased from 277 in 2004 to 761 in 2021 (Belgian Cancer Registry). This indicates the significant rise in incidence of HCC over the past two decades, highlighting the growing public health challenge posed by this disease. The research conducted during this master’s Dissertation contributes to the preclinical research on HCC and presents in vitro data on potential combinations of deubiquitinating enzyme (DUB) inhibitors and FDA-approved drugs in HCC cell lines. The ultimate goal – in line with the societal impact - is to enhance the efficacy of current therapies for patients with advanced HCC, aiming to improve prognoses while maintaining tolerable side effects. Following validation, we hope that in the near future clinical trials can be set up to possibly integrate these enhanced therapies into clinical practice and enhance the quality of life for multiple patients worldwide.