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
Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, P.R. China.
Tianjin's Clinical Research Center for Cancer, Tianjin, P.R. China.
Cancer Res. 2023 Apr 4;83(7):1048-1061. 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.
乙型肝炎病毒（HBV）感染是肝癌发生的主要驱动因素。铁死亡是一种铁介导的细胞死亡，可抑制肝脏转化。先前的研究已将HBV与肝纤维化和急性肝衰竭中的铁死亡联系起来。然而，铁死亡是否参与HBV介导的肝癌尚不清楚。在这里，我们确定热休克蛋白家族A成员8（HSPA8）是一种关键的宿主因子，可调节肝癌中HBV的复制和铁死亡。乙型肝炎X蛋白（HBx）通过在细胞中共激活转录因子热休克因子1（HSF1）上调HSPA8。HSPA8通过将乙型肝炎核心蛋白（HBc）募集到HBV共价闭合环状DNA（cccDNA）微型染色体上增强HBV复制，形成正反馈回路。此外，HSPA8通过上调SLC7A11/GPX4的表达并减少体外和体内细胞中erastin介导的活性氧和Fe2+积累来抑制肝癌细胞中的铁死亡。抑制HSPA8可减少HBV阳性肝肿瘤的生长并增加对erastin的敏感性。总之，HBx升高的HSPA8调节肝癌中HBV的复制和铁死亡。靶向HSPA8可能是控制HBV和肝癌发生的一种有前景的策略。
HBV诱导的HSPA8上调通过抑制铁死亡和刺激HBV复制促进肝癌发生，确定HSPA8为肝癌的潜在治疗靶点。
