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LIVER CANCER / BASIC RESEARCH
Uncovering the role of RPL8 in glutathione synthesis-dependent ferroptosis control in hepatocellular carcinoma
1
Department of Oncology, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, China
2
Department of Ultrasound, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of the Naval Medical University, Shanghai, China
These authors had equal contribution to this work
Submission date: 2024-04-12
Final revision date: 2024-07-19
Acceptance date: 2024-07-30
Online publication date: 2024-08-05
Arch Med Sci 2025;21(4):1513-1535
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Hepatocellular carcinoma (HCC) is significantly impacted by ferroptosis, a form of regulated cell death linked to iron metabolism and oxidative stress. This process is modulated by glutathione (GSH) levels. This study explored the role of ferroptosis-related genes (FRGs) in HCC and evaluated the impact of RPL8 on HCC progression and ferroptosis mechanisms.
Material and methods:
Through comprehensive TCGA-LIHC data analysis, we identified significant FRGs affecting HCC prognosis. The expression and functional significance of RPL8 in HCC were further evaluated using cell line models and tumor xenograft experiments, focusing on its effects on cell proliferation, invasion, migration, apoptosis, and regulation of ferroptosis.
Results:
Elevated RPL8 expression was observed in HCC tissues and cell lines. Functional experimental results showed that RPL8 regulation significantly affects cell proliferation, invasion, migration, and apoptosis. RPL8 silencing significantly inhibited tumor growth in tumor xenograft experiments. Furthermore, RPL8 knockdown resulted in increased 4-HNE levels, indicating increased lipid peroxidation and triggering ferroptosis, which was partially alleviated by inhibitors such as Nec-1, Z-VAD-FMK, and Fer-1. RPL8 was also found to significantly alter the production of glycine, glutamate, and cysteine, upregulate glutathione synthase (GSS) protein levels, and enhance the GSH synthesis pathway.
Conclusions:
RPL8 plays a key role in regulating HCC ferroptosis and tumor progression, affecting cellular defense by regulating GSH synthesis. These insights highlight RPL8 as a promising target for therapeutic intervention in HCC.
Hepatocellular carcinoma (HCC) is significantly impacted by ferroptosis, a form of regulated cell death linked to iron metabolism and oxidative stress. This process is modulated by glutathione (GSH) levels. This study explored the role of ferroptosis-related genes (FRGs) in HCC and evaluated the impact of RPL8 on HCC progression and ferroptosis mechanisms.
Material and methods:
Through comprehensive TCGA-LIHC data analysis, we identified significant FRGs affecting HCC prognosis. The expression and functional significance of RPL8 in HCC were further evaluated using cell line models and tumor xenograft experiments, focusing on its effects on cell proliferation, invasion, migration, apoptosis, and regulation of ferroptosis.
Results:
Elevated RPL8 expression was observed in HCC tissues and cell lines. Functional experimental results showed that RPL8 regulation significantly affects cell proliferation, invasion, migration, and apoptosis. RPL8 silencing significantly inhibited tumor growth in tumor xenograft experiments. Furthermore, RPL8 knockdown resulted in increased 4-HNE levels, indicating increased lipid peroxidation and triggering ferroptosis, which was partially alleviated by inhibitors such as Nec-1, Z-VAD-FMK, and Fer-1. RPL8 was also found to significantly alter the production of glycine, glutamate, and cysteine, upregulate glutathione synthase (GSS) protein levels, and enhance the GSH synthesis pathway.
Conclusions:
RPL8 plays a key role in regulating HCC ferroptosis and tumor progression, affecting cellular defense by regulating GSH synthesis. These insights highlight RPL8 as a promising target for therapeutic intervention in HCC.
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| eISSN: | 1896-9151 |
| ISSN: | 1734-1922 |
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