GRP78/BiP as a novel midbody component induces mitotic exit failure via PLK1 stabilization in hepatocellular...

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide and is associated with a poor prognosis, even when diagnosed in its early stages. Therefore, identifying novel HCC targets for therapeutic drug development is critically needed. Our proteomic analysis identified Glucose-regulated protein 78 (GRP78) as a potential new target, showing enrichment in HCC spheroids. We observed that post-surgery HCC patients with elevated GRP78 expression in non-tumor tissues had an unfavorable prognosis. Inhibition of GRP78 expression suppressed cell proliferation and reduced viability by controlling the DNA damage response in HCC cells. GRP78 expression peaked during the G2/M phase of mitosis and was predominantly localized to the cytoskeleton. However, its expression decreased as the cell cycle progressed from the G2/M to the G1 phase in HCCs. Overexpression of GRP78 in HCC cells increased the interaction between PLK1 and GRP78, leading to the stabilization of PLK1 in the midbody during cytokinesis. This stabilization resulted in the failure of cells to exit mitosis, producing multinucleated HCC cells. These findings reveal novel functional roles for GRP78 in disrupting mitotic activity through the stabilization of PLK1 at the midbody, thereby fostering polyploidy development in HCC. This suggests that inhibiting GRP78 is a promising approach for enhancing HCC therapy. [BMB Reports 2026; 59(8): 398-406].