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

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 i...

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Vydáno v:Cancer research (Chicago, Ill.) Ročník 83; číslo 7; s. 1048
Hlavní autoři: 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
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 04.04.2023
Témata:
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:1538-7445, 1538-7445
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Shrnutí: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.
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ISSN:1538-7445
1538-7445
DOI:10.1158/0008-5472.CAN-22-3169