HBx-Induced HSPA8 Stimulates HBV Replication and Suppresses Ferroptosis to Support Liver Cancer Progression

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (7), p.1048-1061
• Main Authors: Wang, Yufei, Zhao, Man, Zhao, Lina, Geng, Yu, Li, Guanghao, Chen, Lin, Yu, Jingxuan, Yuan, Hongfeng, Zhang, Huihui, Yun, Haolin, Yuan, Ying, Wang, Guowen, Feng, Jinyan, Xu, Liang, Wang, Shuai, Hou, Chunyu, Yang, Guang, Zhang, Ningning, Lu, Wei, Zhang, Xiaodong
• Format: Article
• Language: English
• Subjects: DNA, Circular - metabolism; Ferroptosis; Hep G2 Cells; Hepatitis B - complications; Hepatitis B virus - genetics; Hepatitis B virus - metabolism; HSC70 Heat-Shock Proteins - genetics; HSC70 Heat-Shock Proteins - metabolism; Humans; Liver Neoplasms - genetics; Virus Replication - genetics
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-22-3169

Hepatitis B virus (HBV) infection is a major driver of hepatocarcinogenesis. Ferroptosis is a type of iron-mediated cell death that can suppress liver transformation. Previous studies have linked HBV to ferroptosis in liver fibrosis and acute liver failure. However, whether ferroptosis is involved in HBV-mediated liver cancer is poorly understood. Here, we identified heat shock protein family A member 8 (HSPA8) as a crucial host factor that modulates HBV replication and ferroptosis in liver cancer. Hepatitis B X protein (HBx) upregulated HSPA8 by coactivating the transcription factor heat shock factor 1 (HSF1) in cells. HSPA8 enhanced HBV replication by recruiting hepatitis B core protein (HBc) to the HBV covalently closed circular DNA (cccDNA) minichromosome, forming a positive feedback loop. Moreover, HSPA8 suppressed ferroptosis in liver cancer cells by upregulating the expression of SLC7A11/GPX4 and decreasing erastin-mediated reactive oxygen species and Fe2+ accumulation in cells in vitro and in vivo. Inhibition of HSPA8 reduced the growth of HBV-positive liver tumors and increased sensitivity to erastin. In conclusion, HBx-elevated HSPA8 regulates both HBV replication and ferroptosis in liver cancer. Targeting HSPA8 could be a promising strategy for controlling HBV and hepatocarcinogenesis. HBV-induced upregulation of HSPA8 promotes hepatocarcinogenesis by suppressing ferroptosis and stimulating HBV replication, identifying HSPA8 as a potential therapeutic target in liver cancer.