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Introduction: Hepatocellular carcinoma (HCC) is a form of liver cancer seen in those with long-term liver disease and is one of the leading causes of cancer mortality globally. Current standard of care has been ineffective at reducing tumor burden and improving patient outcomes, in addition to causing many serious and detrimental side effects. With correlations to prostate cancer (PCa), increased expression and activity of androgen receptor (AR) signaling by AR-full length (AR-FL) and AR splice variants (AR-SVs) have been suggested to promote HCC progression. We investigate a new approach to mitigating AR signaling in HCC through AR degraders, specifically Selective Androgen Receptor Degraders (SARDs) and Proteolysis Targeting Chimeric (PROTAC) molecules. Objective/Hypothesis: To evaluate androgen receptor (AR) antagonism with AR degrader compounds in AR(+) HCC. We hypothesize that AR degraders ARV-110 and UT-155 will exhibit anti-HCC effects by reducing cell growth, tumor development, and transcriptional activity in AR(+) HCC. Methods: To examine AR protein levels following treatment with AR-FL degraders UT-155 and ARV-110, we performed an immunoblot analysis on AR-FL(+) HCC cells. We then conducted cell viability assays to investigate anti-HCC effects on AR-FL(+) HCC cells. To determine if AR degradation blocks AR signaling in AR-FL(+)/AR-SV(+) HCC, we examined AR protein levels and AR-dependent cell viability following treatment of AR degraders in AR-FL(+)/AR-SV(+) HCC cells. Results: We showed lower AR-FL protein levels with UT-155 and ARV-110 in AR-FL(+) HCC cells. AR-FL degradation resulted in lower cell viability for higher concentrations of UT-155, but minimal reduction in cell viability with ARV-110 treatment after 24 hours in AR-FL(+) HCC cells. Due to UT-155 also binding outside of the traditional LBD in the AR enabling it to target AR-SVs, we expected reduced cell viability in AR-FL(+)/AR-SV(+) HCC. However, expected effects in AR-FL(+)/AR-SV(+) cells following ARV-110 treatment were unclear given its requirement to interact with the AR-LBD. Anti-HCC effects were seen in AR-FL(+)/AR-SV(+) HCC upon treatment with UT-155 but not with ARV-110. Conclusion: Despite different mechanisms of degradation, AR degraders UT-155 and ARV-110 demonstrated some reduced AR protein levels in AR(+) prostate cancer and HCC cells. However, with UT-155’s overt cytotoxicity, reduced AR protein expression seen in SNU423 AR-FL(+) HCC cells may be due to non-specific effects associated with cell death. As for ARV-110, the reduction in AR protein level with minimal cytotoxicity suggests AR specificity, which is important for avoiding toxicity in non-AR expressing cells. We will continue investigations of AR degraders on invasion potential and AR specificity in future studies.