USP54 regulates RIPK1 protein abundance via deubiquitination in acquired sorafenib resistance in hepatocellular carcinoma

Abstract Ubiquitin-specific peptidase 54 (USP54) is a member of the deubiquitinating enzyme family and is involved in the regulation of protein deubiquitination. Deubiquitination plays a crucial role in hepatocellular carcinoma (HCC), but the relationship between USP54 and HCC remains unclear. This study demonstrates that USP54 is aberrantly overexpressed in hepatocellular carcinoma, with further elevated expression in sorafenib-resistant cell lines. USP54 knockdown significantly increased the sensitivity of HCC cells to sorafenib in vitro, while its potential to enhance sorafenib response in vivo was suggested by the reduced tumor growth observed during sorafenib treatment. In sorafenib-resistant cells, USP54 knockdown increased RIPK1 ubiquitination, supporting a role for USP54 in regulating RIPK1 deubiquitination. Moreover, RIPK1 knockdown attenuated sorafenib resistance even in USP54-overexpressing HCC cells. This indicates that USP54 may promote the deubiquitination of RIPK1, thereby stabilising RIPK1 and activating its downstream signalling pathways, thus facilitating sorafenib resistance in hepatocellular carcinoma. These findings suggest an association between USP54 and the progression of HCC, as well as sorafenib resistance, thereby providing a potential novel target for addressing sorafenib resistance in HCC.