Targeting Sodium Transport Reveals CHP1 Downregulation as a Novel Molecular Feature of Malignant Progression in Clear Cell Renal Cell Carcinoma: Insights from Integrated Multi-Omics Analyses
Clear cell renal cell carcinoma (ccRCC), the most common RCC subtype, displays significant intratumoral heterogeneity driven by metabolic reprogramming, which complicates our understanding of disease progression and limits treatment efficacy. This study aimed to construct a comprehensive cellular an...
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2025-07-01
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| author | Yun Wu Ri-Ting Zhu Jia-Ru Chen Xiao-Min Liu Guo-Liang Huang Jin-Cheng Zeng Hong-Bing Yu Xin Liu Cui-Fang Han |
| author_facet | Yun Wu Ri-Ting Zhu Jia-Ru Chen Xiao-Min Liu Guo-Liang Huang Jin-Cheng Zeng Hong-Bing Yu Xin Liu Cui-Fang Han |
| author_sort | Yun Wu |
| collection | DOAJ |
| description | Clear cell renal cell carcinoma (ccRCC), the most common RCC subtype, displays significant intratumoral heterogeneity driven by metabolic reprogramming, which complicates our understanding of disease progression and limits treatment efficacy. This study aimed to construct a comprehensive cellular and transcriptional landscape of ccRCC, with emphasis on gene expression dynamics during malignant progression. An integrated analysis of 90 scRNA-seq samples comprising 534,227 cells revealed a progressive downregulation of sodium ion transport-related genes, particularly CHP1 (calcineurin B homologous protein isoform 1), which is predominantly expressed in epithelial cells. Reduced CHP1 expression was confirmed at both mRNA and protein levels using bulk RNA-seq, CPTAC proteomics, immunohistochemistry, and ccRCC cell lines. Survival analysis showed that high CHP1 expression correlated with improved prognosis. Functional analyses, including pseudotime trajectory, Mfuzz clustering, and cell–cell communication modeling, indicated that CHP1<sup>+</sup> epithelial cells engage in immune interaction via PPIA–BSG signaling. Transcriptomic profiling and molecular docking suggested that CHP1 modulates amino acid transport through SLC38A1. ZNF460 was identified as a potential transcription factor of CHP1. Virtual screening identified arbutin and imatinib mesylate as candidate CHP1-targeting compounds. These findings establish CHP1 downregulation as a novel molecular feature of ccRCC progression and support its utility as a prognostic biomarker. |
| format | Article |
| id | doaj-art-de9cd305b1834c91925802888b8231f4 |
| institution | DOAJ |
| issn | 2218-273X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-de9cd305b1834c91925802888b8231f42025-08-20T03:08:05ZengMDPI AGBiomolecules2218-273X2025-07-01157101910.3390/biom15071019Targeting Sodium Transport Reveals CHP1 Downregulation as a Novel Molecular Feature of Malignant Progression in Clear Cell Renal Cell Carcinoma: Insights from Integrated Multi-Omics AnalysesYun Wu0Ri-Ting Zhu1Jia-Ru Chen2Xiao-Min Liu3Guo-Liang Huang4Jin-Cheng Zeng5Hong-Bing Yu6Xin Liu7Cui-Fang Han8Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, ChinaGuangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, ChinaGuangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, ChinaGuangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, ChinaGuangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, ChinaGuangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, ChinaGuangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, ChinaDongguan Key Laboratory of Public Health Laboratory Science, School of Public Health, Guangdong Medical University, Dongguan 523808, ChinaGuangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, ChinaClear cell renal cell carcinoma (ccRCC), the most common RCC subtype, displays significant intratumoral heterogeneity driven by metabolic reprogramming, which complicates our understanding of disease progression and limits treatment efficacy. This study aimed to construct a comprehensive cellular and transcriptional landscape of ccRCC, with emphasis on gene expression dynamics during malignant progression. An integrated analysis of 90 scRNA-seq samples comprising 534,227 cells revealed a progressive downregulation of sodium ion transport-related genes, particularly CHP1 (calcineurin B homologous protein isoform 1), which is predominantly expressed in epithelial cells. Reduced CHP1 expression was confirmed at both mRNA and protein levels using bulk RNA-seq, CPTAC proteomics, immunohistochemistry, and ccRCC cell lines. Survival analysis showed that high CHP1 expression correlated with improved prognosis. Functional analyses, including pseudotime trajectory, Mfuzz clustering, and cell–cell communication modeling, indicated that CHP1<sup>+</sup> epithelial cells engage in immune interaction via PPIA–BSG signaling. Transcriptomic profiling and molecular docking suggested that CHP1 modulates amino acid transport through SLC38A1. ZNF460 was identified as a potential transcription factor of CHP1. Virtual screening identified arbutin and imatinib mesylate as candidate CHP1-targeting compounds. These findings establish CHP1 downregulation as a novel molecular feature of ccRCC progression and support its utility as a prognostic biomarker.https://www.mdpi.com/2218-273X/15/7/1019clear cell renal cell carcinomacalcineurin B homologous protein isoform 1single-cell RNA sequencingtumor microenvironmentsodium transportprognostic biomarker |
| spellingShingle | Yun Wu Ri-Ting Zhu Jia-Ru Chen Xiao-Min Liu Guo-Liang Huang Jin-Cheng Zeng Hong-Bing Yu Xin Liu Cui-Fang Han Targeting Sodium Transport Reveals CHP1 Downregulation as a Novel Molecular Feature of Malignant Progression in Clear Cell Renal Cell Carcinoma: Insights from Integrated Multi-Omics Analyses Biomolecules clear cell renal cell carcinoma calcineurin B homologous protein isoform 1 single-cell RNA sequencing tumor microenvironment sodium transport prognostic biomarker |
| title | Targeting Sodium Transport Reveals CHP1 Downregulation as a Novel Molecular Feature of Malignant Progression in Clear Cell Renal Cell Carcinoma: Insights from Integrated Multi-Omics Analyses |
| title_full | Targeting Sodium Transport Reveals CHP1 Downregulation as a Novel Molecular Feature of Malignant Progression in Clear Cell Renal Cell Carcinoma: Insights from Integrated Multi-Omics Analyses |
| title_fullStr | Targeting Sodium Transport Reveals CHP1 Downregulation as a Novel Molecular Feature of Malignant Progression in Clear Cell Renal Cell Carcinoma: Insights from Integrated Multi-Omics Analyses |
| title_full_unstemmed | Targeting Sodium Transport Reveals CHP1 Downregulation as a Novel Molecular Feature of Malignant Progression in Clear Cell Renal Cell Carcinoma: Insights from Integrated Multi-Omics Analyses |
| title_short | Targeting Sodium Transport Reveals CHP1 Downregulation as a Novel Molecular Feature of Malignant Progression in Clear Cell Renal Cell Carcinoma: Insights from Integrated Multi-Omics Analyses |
| title_sort | targeting sodium transport reveals chp1 downregulation as a novel molecular feature of malignant progression in clear cell renal cell carcinoma insights from integrated multi omics analyses |
| topic | clear cell renal cell carcinoma calcineurin B homologous protein isoform 1 single-cell RNA sequencing tumor microenvironment sodium transport prognostic biomarker |
| url | https://www.mdpi.com/2218-273X/15/7/1019 |
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