HBx-induced HSPA8 stimulates HBV replication and suppresses ferroptosis to support liver cancer progression

  • Cancer Res. 2023 Feb 6;CAN-22-3169. doi: 10.1158/0008-5472.CAN-22-3169.
Yufei Wang  1 ,  Man Zhao  2 ,  Lina Zhao  1 ,  Yu Geng  3 ,  Guanghao Li  4 ,  Lin Chen  5 ,  Jingxuan Yu  3 ,  Hongfeng Yuan  2 ,  Huihui Zhang  1 ,  Haolin Yun  2 ,  Ying Yuan  2 ,  Guowen Wang  4 ,  Jinyan Feng  6 ,  Liang Xu  7 ,  Shuai Wang  4 ,  Chunyu Hou  8 ,  Guang Yang  1 ,  Ning-Ning Zhang  1 ,  Wei Lu  1 ,  Xiaodong Zhang  1
Affiliations
  • 1. Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  • 2. Nankai University, Tianjin, China.
  • 3. Nankai University, China.
  • 4. Tianjin Medical University Cancer Institute and Hospital, China.
  • 5. Tianjin Second People's Hospital, China.
  • 6. Tianjin Medical University Cancer Institute and Hospital, tianjin, China.
  • 7. Tianjin Second People's Hospital, Tianjin, China.
  • 8. Tianjin Medical University Cancer Institute and Hospital, Tianjin, Tianjin, China.
PMID: 36745032 DOI: 10.1158/0008-5472.CAN-22-3169
Abstract

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 expression of SLC7A11/GPX4 and decreasing erastin-mediated ROS 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.

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