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UXS1 Knockdown Suppresses Cell Proliferation and Invasion in Hepatocellular Carcinoma by Inducing Ferroptosis via
Jun Lv1, Kang Han2, Fu-Yuan Gan2
1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China. yfy004219@sr.gxmu.edu.cn.
Objective:
Identifying novel molecular drivers is crucial to improving therapeutic strategies for hepatocellular carcinoma (HCC). This study aimed to investigate the clinical significance and biological function of UDP-glucuronate decarboxylase 1 (UXS1) in HCC.
Methods:
UXS1 expression and its prognostic value were analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA) database. In vitro, UXS1 was silenced in Huh-7 and HCCLM3 cell lines via siRNA. Malignant phenotypes were evaluated using CCK-8, Transwell, and wound healing assays. Transcriptome sequencing (RNA-seq) was performed to identify downstream mechanisms. Additionally, oxidative stress markers (catalase, superoxide dismutase, and glutathione) and key ferroptosis regulators (GPX4, SLC7A11) were assessed. Notably, rescue experiments using the ferroptosis inhibitor Ferrostatin-1 were conducted to validate the mechanism.
Results:
UXS1 mRNA expression was significantly upregulated in HCC tissues, and high expression correlated with poor overall and progression-free survival. Functionally, UXS1 knockdown significantly inhibited HCC cell proliferation, migration, and invasion. Transcriptome analysis of 425 differentially expressed genes (DEGs) highlighted the enrichment of reactive oxygen species (ROS) and ferroptosis-related pathways. Mechanistically, UXS1 silencing disrupted ROS homeostasis and downregulated the anti-ferroptotic proteins GPX4 and SLC7A11. Significantly, treatment with Ferrostatin-1 effectively reversed the tumor-suppressive effects of UXS1 knockdown.
Conclusion:
High expression of UXS1 serves as a prognostic biomarker for HCC. UXS1 knockdown suppresses HCC malignant progression, at least partially, by inducing ferroptosis via the SLC7A11/GPX4 axis. These findings suggest UXS1 is a potential therapeutic target and a novel ferroptosis checkpoint in HCC.
Insights
High UDP-glucuronate decarboxylase 1 (UXS1) expression predicts poor outcomes in hepatocellular carcinoma (HCC). Silencing UXS1 inhibits HCC progression by inducing ferroptosis, suggesting UXS1 is a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide.
- Identifying novel molecular drivers is critical for developing effective therapeutic strategies against HCC.
- UDP-glucuronate decarboxylase 1 (UXS1) has emerged as a potential factor in cancer progression.
Purpose of the Study:
- To investigate the clinical significance of UDP-glucuronate decarboxylase 1 (UXS1) in hepatocellular carcinoma (HCC).
- To elucidate the biological function and underlying mechanisms of UXS1 in HCC progression.
- To evaluate UXS1 as a potential prognostic biomarker and therapeutic target in HCC.
Main Methods:
- Analyzed UXS1 expression and prognostic value using the Gene Expression Profiling Interactive Analysis (GEPIA) database.
- Performed in vitro knockdown of UXS1 in HCC cell lines (Huh-7, HCCLM3) using siRNA.
- Assessed malignant phenotypes (proliferation, migration, invasion), transcriptome (RNA-seq), oxidative stress markers, and ferroptosis regulators (GPX4, SLC7A11).
- Conducted rescue experiments with Ferrostatin-1 to validate the ferroptosis mechanism.
Main Results:
- UXS1 mRNA expression was significantly upregulated in HCC tissues, correlating with poorer overall and progression-free survival.
- UXS1 knockdown suppressed HCC cell proliferation, migration, and invasion.
- Transcriptome analysis revealed enrichment of reactive oxygen species (ROS) and ferroptosis pathways.
- UXS1 silencing disrupted ROS homeostasis and downregulated GPX4 and SLC7A11, key ferroptosis regulators.
- Ferrostatin-1 treatment reversed the tumor-suppressive effects of UXS1 knockdown, confirming ferroptosis induction.
Conclusions:
- Elevated UXS1 expression serves as a significant prognostic biomarker for HCC patients.
- Knockdown of UXS1 inhibits HCC progression, partly by inducing ferroptosis through the SLC7A11/GPX4 axis.
- UXS1 represents a promising therapeutic target and a novel ferroptosis checkpoint in HCC treatment strategies.
