Hepatocellular carcinoma (HCC) is the most common digestive malignancy, ranking the sixth-most prevalent cancer and the fourth leading cause of cancer-related mortality in the world(Sung et al., 2021).Most patients with HCC are diagnosed at advanced stage due to the asymptomatic nature at early stage. Based on the 2022Barcelona Clinic Liver Cancer (BCLC) treatment strategy, it is recommended patients with advanced stage HCC to receive systemic drug treatment, including chemotherapy, targeted therapy, and immunotherapy(Reig et al., 2022).Unfortunately, the therapeutic efficacy is modest, and most patients do notexperience a long-term benefit, largely due to the occurrence of primary or acquired drug resistance(Lee et al., 2022; Xia et al., 2020).

The substantialheterogeneity of HCCis considered as the cause of drug resistance. Hepatic cancer stem cells (CSCs) account for a small subset of tumor cells with long-term tumorigenic capacity which contribute to phenotypic diversity ofHCC cells. CSCsplay an important role in primary drug resistance of tumors and acquired drug resistance during long-term drug exposure(Chen et al., 2019b; Xiang et al., 2019).In this context,specificallytargeting CSCs may improve the therapeutic efficacy incancers.A series of potential therapeutics based on targeting CSCsare currently under development, includingthosetargeting CSC surface biomarkers, CSCsignaling pathways, CSC niche, and others. In this paper, we review drug resistance in HCC, and provide a summary of potential targets for CSCs-based therapy, and the development of CSCs-targeted therapeutics against drug resistance in HCC.The in-depth understanding of CSCs in HCC will favor optimization ofthe current therapeutic strategies and gain encouraging therapeutic outcomes.