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

• DOI: 10.1158/0008-5472.c.6514397.v1
• Publication Date: 2023-03-31T21:10:11Z
• Authors: Yufei Wang; Man Zhao; Lina Zhao; Yu Geng; Guanghao Li; Lin Chen; Jingxuan Yu; Hongfeng Yuan; Huihui Zhang; Haolin Yun; Ying Yuan; Guowen Wang; Jinyan Feng; Liang Xu; Shuai Wang; Chunyu Hou; Guang Yang; Ningning Zhang; Wei Lu; Xiaodong Zhang

<div>Abstract<p>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 <i>in vitro</i> and <i>in vivo</i>. 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.</p>Significance:<p>HBV-induced upregulation of HSPA8 promotes hepatocarcinogenesis by suppressing ferroptosis and stimulating HBV replication, identifying HSPA8 as a potential therapeutic target in liver cancer.</p></div>