Bioinformatics Identification of Lactate‐Associated Genes in Hepatocellular Carcinoma: G6PD's Role in Immune Modulation
ABSTRACT Background Hepatocellular carcinoma (HCC) is a major global health issue, with poor prognosis often associated with dysregulated metabolic pathways, especially lactate metabolism. This study explored the prognostic significance of lactate‐associated genes in HCC and their potential as thera...
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Wiley
2025-03-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.70801 |
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| author | Hao‐ran Qu Chao‐qun Wang Su‐juan Sun Wen‐wen Zhang Cheng‐hao Liu Xuan‐shuang Du Yao‐yi‐ao Shu Xi‐cheng Wang Qin Pan Feng‐ling Luo Hong‐yan Wu Xiao‐lian Zhang Min Liu |
| author_facet | Hao‐ran Qu Chao‐qun Wang Su‐juan Sun Wen‐wen Zhang Cheng‐hao Liu Xuan‐shuang Du Yao‐yi‐ao Shu Xi‐cheng Wang Qin Pan Feng‐ling Luo Hong‐yan Wu Xiao‐lian Zhang Min Liu |
| author_sort | Hao‐ran Qu |
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| description | ABSTRACT Background Hepatocellular carcinoma (HCC) is a major global health issue, with poor prognosis often associated with dysregulated metabolic pathways, especially lactate metabolism. This study explored the prognostic significance of lactate‐associated genes in HCC and their potential as therapeutic targets. Methods We analyzed RNA‐seq and clinical data from 374 patients with HCC from The Cancer Genome Atlas (TCGA) database. Using Cox regression, LASSO analysis, and Kaplan–Meier survival curves, we identified key lactate‐associated genes associated with patient outcomes. Functional validations, including Western blot, flow cytometry, and molecular docking studies, were performed to confirm the biological impact of these genes. Results G6PD, IK, and CALML5 were identified as significant prognostic markers for HCC. A prognostic model was developed that effectively stratified patients into risk groups, which correlated with survival. G6PD's role in immune modulation and its potential as a drug target were validated through biochemical assays and computational analyses. Functional assays in HepG2 cells confirmed that alterations in G6PD expression affect T cell activity, with knockdown enhancing IFN‐γ production and overexpression inhibiting it, demonstrating G6PD's role in immune evasion. Conclusions This study establishes lactate metabolism genes, particularly G6PD, as key prognostic markers in HCC. The validation of G6PD's immunomodulatory effects further supports its potential as a therapeutic target for strategies aimed at enhancing immune surveillance and treatment outcomes in HCC. |
| format | Article |
| id | doaj-art-36548eb07d704ee09432a3c65ee50c1e |
| institution | OA Journals |
| issn | 2045-7634 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-36548eb07d704ee09432a3c65ee50c1e2025-08-20T02:26:31ZengWileyCancer Medicine2045-76342025-03-01146n/an/a10.1002/cam4.70801Bioinformatics Identification of Lactate‐Associated Genes in Hepatocellular Carcinoma: G6PD's Role in Immune ModulationHao‐ran Qu0Chao‐qun Wang1Su‐juan Sun2Wen‐wen Zhang3Cheng‐hao Liu4Xuan‐shuang Du5Yao‐yi‐ao Shu6Xi‐cheng Wang7Qin Pan8Feng‐ling Luo9Hong‐yan Wu10Xiao‐lian Zhang11Min Liu12State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences) Wuhan University Wuhan ChinaDepartment of Neurosurgery Renmin Hospital of Wuhan University Wuhan ChinaState Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences) Wuhan University Wuhan ChinaState Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences) Wuhan University Wuhan ChinaState Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences) Wuhan University Wuhan ChinaState Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences) Wuhan University Wuhan ChinaDepartment of Neurosurgery Renmin Hospital of Wuhan University Wuhan ChinaDepartment of Neurosurgery Renmin Hospital of Wuhan University Wuhan ChinaState Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences) Wuhan University Wuhan ChinaState Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences) Wuhan University Wuhan ChinaHubei Key Laboratory of Tumor Microenvironment and Immunotherapy China Three Gorges University Yichang ChinaState Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences) Wuhan University Wuhan ChinaState Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences) Wuhan University Wuhan ChinaABSTRACT Background Hepatocellular carcinoma (HCC) is a major global health issue, with poor prognosis often associated with dysregulated metabolic pathways, especially lactate metabolism. This study explored the prognostic significance of lactate‐associated genes in HCC and their potential as therapeutic targets. Methods We analyzed RNA‐seq and clinical data from 374 patients with HCC from The Cancer Genome Atlas (TCGA) database. Using Cox regression, LASSO analysis, and Kaplan–Meier survival curves, we identified key lactate‐associated genes associated with patient outcomes. Functional validations, including Western blot, flow cytometry, and molecular docking studies, were performed to confirm the biological impact of these genes. Results G6PD, IK, and CALML5 were identified as significant prognostic markers for HCC. A prognostic model was developed that effectively stratified patients into risk groups, which correlated with survival. G6PD's role in immune modulation and its potential as a drug target were validated through biochemical assays and computational analyses. Functional assays in HepG2 cells confirmed that alterations in G6PD expression affect T cell activity, with knockdown enhancing IFN‐γ production and overexpression inhibiting it, demonstrating G6PD's role in immune evasion. Conclusions This study establishes lactate metabolism genes, particularly G6PD, as key prognostic markers in HCC. The validation of G6PD's immunomodulatory effects further supports its potential as a therapeutic target for strategies aimed at enhancing immune surveillance and treatment outcomes in HCC.https://doi.org/10.1002/cam4.70801G6PDhepatocellular carcinomalactate metabolismPD‐L1prognostic biomarkers |
| spellingShingle | Hao‐ran Qu Chao‐qun Wang Su‐juan Sun Wen‐wen Zhang Cheng‐hao Liu Xuan‐shuang Du Yao‐yi‐ao Shu Xi‐cheng Wang Qin Pan Feng‐ling Luo Hong‐yan Wu Xiao‐lian Zhang Min Liu Bioinformatics Identification of Lactate‐Associated Genes in Hepatocellular Carcinoma: G6PD's Role in Immune Modulation Cancer Medicine G6PD hepatocellular carcinoma lactate metabolism PD‐L1 prognostic biomarkers |
| title | Bioinformatics Identification of Lactate‐Associated Genes in Hepatocellular Carcinoma: G6PD's Role in Immune Modulation |
| title_full | Bioinformatics Identification of Lactate‐Associated Genes in Hepatocellular Carcinoma: G6PD's Role in Immune Modulation |
| title_fullStr | Bioinformatics Identification of Lactate‐Associated Genes in Hepatocellular Carcinoma: G6PD's Role in Immune Modulation |
| title_full_unstemmed | Bioinformatics Identification of Lactate‐Associated Genes in Hepatocellular Carcinoma: G6PD's Role in Immune Modulation |
| title_short | Bioinformatics Identification of Lactate‐Associated Genes in Hepatocellular Carcinoma: G6PD's Role in Immune Modulation |
| title_sort | bioinformatics identification of lactate associated genes in hepatocellular carcinoma g6pd s role in immune modulation |
| topic | G6PD hepatocellular carcinoma lactate metabolism PD‐L1 prognostic biomarkers |
| url | https://doi.org/10.1002/cam4.70801 |
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