Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide.
Chemoresistance remains the major factor for limited efficacy of the HCC treatment. Thus, exploring
the mechanisms underlying drug resistance is of great importance. Secretory clusterin (sCLU), a stressactivated
and ATP-independent molecular chaperone, is up-regulated in numerous tumors and correlated
with malignant phenotypes. For HCC, the implication of sCLU was previously addressed in tumor
growth, metastasis, as well as early diagnosis and poor prognosis. Notably, accumulating studies
have emphasized its vital role in drug resistance of HCC. Depletion of sCLU synergistically could enhance
the sensitivity of HCC cells to a variety of chemotherapy agents. Herein, we summarized the potential
mechanisms accounting for the sCLU-induced chemoresistance, including promoting apoptosis
evasion, facilitating epithelial-mesenchymal transition (EMT), maintaining the viability of cancer stem
cell (CSC), enhancing drug efflux capacity, and regulating autophagic activities. The current evidence
suggest that targeting sCLU might be a promising approach in overcoming chemoresistance of HCC.