XBP1 as a novel molecular target to attenuate drug resistance in hepatocellular carcinoma

Despite improvements in clinical management of hepatocellular carcinoma (HCC), prognosis remains poor with a 5-year survival rate less than 40%. Drug resistance in HCC makes it challenging to treat; therefore, it is imperative to develop new therapeutic strategies. Higher expression of X-box binding protein 1 (XBP1) in tumor cells is highly correlated with poor prognosis. In tumor cells, XBP1 modulates the unfolded protein response (UPR) to restore homeostasis in endoplasmic reticulum. Targeting XBP1 could be a promising therapeutic strategy to overcome HCC resistance and improve the survival rate of patients.

This review provides the recent evidence that indicates XBP1 is involved in HCC drug resistance via DNA damage response, drug inactivation, and inhibition of apoptosis. In addition, the potential roles of XBP1 in inducing resistance in HCC cells were highlighted, and we showed how its inhibition could sensitize tumor cells to controlled cell death.

Due to the diversity in molecular mechanism of multidrug-resistance, targeting one specific pathway is inadequate. XBP1 inhibition could be a potential therapeutic target to overcome verity of resistance mechanisms. The main function of this transcription factor in HCC treatment response is an attractive area for further studies and should be discussed more.