Unveiling ammonia-induced cell death: a new frontier in clear cell renal cell carcinoma prognosis
BackgroundClear cell renal cell carcinoma (KIRC) is the most aggressive renal carcinoma subtype of renal carcinoma, characterized by high mortality, early metastasis, and resistance to treatment. Ammonia-induced cell death (AICD) has recently been identified as a novel metabolic mechanism influencin...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1636977/full |
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| author | Peize Yu Peize Yu Qikai Zhong Qikai Zhong Xinlei Wang Xinlei Wang Yifang Liu Qiang Liu Qiang Liu Yuqiang Zhang Jiawei Lu Yang Dong Cong-hui Han Cong-hui Han |
| author_facet | Peize Yu Peize Yu Qikai Zhong Qikai Zhong Xinlei Wang Xinlei Wang Yifang Liu Qiang Liu Qiang Liu Yuqiang Zhang Jiawei Lu Yang Dong Cong-hui Han Cong-hui Han |
| author_sort | Peize Yu |
| collection | DOAJ |
| description | BackgroundClear cell renal cell carcinoma (KIRC) is the most aggressive renal carcinoma subtype of renal carcinoma, characterized by high mortality, early metastasis, and resistance to treatment. Ammonia-induced cell death (AICD) has recently been identified as a novel metabolic mechanism influencing tumor progression, yet its prognostic implication and regulatory networks in KIRC remain underexplored.MethodsTranscriptomic and clinical information from the TCGA-KIRC cohort and the validation cohort (E-MTAB-1980) were analyzed. Differentially expressed AICD-related genes were identified through differential expression analysis, univariate Cox regression, and machine learning algorithms (LASSO, random forest, and CoxBoost). A prognostic risk model was developed via multivariate Cox regression. Spatial and single-cell transcriptomics were employed to characterize the immune microenvironment heterogeneity. Cell-based experiments were performed to investigate the potential involvement of ATP1A1 in KIRC. Molecular docking and pan-cancer analyses were conducted to identify therapeutic candidates and ATP1A1-related mechanisms.ResultsFive AICD-related genes (FOXM1, ANK3, ATP1A1, HADH, and PLG) were identified and selected to construct a risk score model. The model demonstrated high accuracy and was integrated into a nomogram for clinical application. High-risk (HR) patients exhibited immunosuppressive microenvironments, elevated tumor mutational burden (TMB), and genomic instability. In vitro functional assays confirmed that ATP1A1 knockdown significantly enhanced the proliferative, migratory, and invasive capabilities of renal carcinoma cells (A498 and 786-O), suggesting a suppressive role for ATP1A1 in malignant tumor progression. ATP1A1, a core gene, was associated with metabolic reprogramming and chemotherapy sensitivity across multiple cancers. Molecular docking revealed Emodinanthrone as a high-affinity ligand for ATP1A1 (−6.8 kcal/mol).ConclusionThis study identifies an AICD-associated gene signature as a robust prognostic tool for KIRC, revealing its interactions with immune evasion and genomic instability. ATP1A1 is proposed as a promising therapeutic target, with Emodinanthrone emerging as a novel drug candidate. These findings contribute to the advancement of personalized treatment strategies for KIRC patients. |
| format | Article |
| id | doaj-art-a2f2cdc266714a3d93d8551436c82e6f |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-a2f2cdc266714a3d93d8551436c82e6f2025-08-20T02:46:24ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-07-011610.3389/fimmu.2025.16369771636977Unveiling ammonia-induced cell death: a new frontier in clear cell renal cell carcinoma prognosisPeize Yu0Peize Yu1Qikai Zhong2Qikai Zhong3Xinlei Wang4Xinlei Wang5Yifang Liu6Qiang Liu7Qiang Liu8Yuqiang Zhang9Jiawei Lu10Yang Dong11Cong-hui Han12Cong-hui Han13Department of Urology, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, ChinaDepartment of Urology, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, ChinaDepartment of Urology, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaJiangsu Key Laboratory of New Drug Research and ClinicalPharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Central Laboratory, Engineering Research Center of Cancer Cell Therapy and Translational Medicine, Xuzhou, Jiangsu, ChinaDepartment of Urology, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, ChinaDepartment of Urology, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Urology, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, ChinaDepartment of Urology, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, ChinaBackgroundClear cell renal cell carcinoma (KIRC) is the most aggressive renal carcinoma subtype of renal carcinoma, characterized by high mortality, early metastasis, and resistance to treatment. Ammonia-induced cell death (AICD) has recently been identified as a novel metabolic mechanism influencing tumor progression, yet its prognostic implication and regulatory networks in KIRC remain underexplored.MethodsTranscriptomic and clinical information from the TCGA-KIRC cohort and the validation cohort (E-MTAB-1980) were analyzed. Differentially expressed AICD-related genes were identified through differential expression analysis, univariate Cox regression, and machine learning algorithms (LASSO, random forest, and CoxBoost). A prognostic risk model was developed via multivariate Cox regression. Spatial and single-cell transcriptomics were employed to characterize the immune microenvironment heterogeneity. Cell-based experiments were performed to investigate the potential involvement of ATP1A1 in KIRC. Molecular docking and pan-cancer analyses were conducted to identify therapeutic candidates and ATP1A1-related mechanisms.ResultsFive AICD-related genes (FOXM1, ANK3, ATP1A1, HADH, and PLG) were identified and selected to construct a risk score model. The model demonstrated high accuracy and was integrated into a nomogram for clinical application. High-risk (HR) patients exhibited immunosuppressive microenvironments, elevated tumor mutational burden (TMB), and genomic instability. In vitro functional assays confirmed that ATP1A1 knockdown significantly enhanced the proliferative, migratory, and invasive capabilities of renal carcinoma cells (A498 and 786-O), suggesting a suppressive role for ATP1A1 in malignant tumor progression. ATP1A1, a core gene, was associated with metabolic reprogramming and chemotherapy sensitivity across multiple cancers. Molecular docking revealed Emodinanthrone as a high-affinity ligand for ATP1A1 (−6.8 kcal/mol).ConclusionThis study identifies an AICD-associated gene signature as a robust prognostic tool for KIRC, revealing its interactions with immune evasion and genomic instability. ATP1A1 is proposed as a promising therapeutic target, with Emodinanthrone emerging as a novel drug candidate. These findings contribute to the advancement of personalized treatment strategies for KIRC patients.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1636977/fullclear cell renal cell carcinomaammonia-induced cell deathprognostic risk modelATP1A1metabolic reprogrammingimmune microenvironment |
| spellingShingle | Peize Yu Peize Yu Qikai Zhong Qikai Zhong Xinlei Wang Xinlei Wang Yifang Liu Qiang Liu Qiang Liu Yuqiang Zhang Jiawei Lu Yang Dong Cong-hui Han Cong-hui Han Unveiling ammonia-induced cell death: a new frontier in clear cell renal cell carcinoma prognosis Frontiers in Immunology clear cell renal cell carcinoma ammonia-induced cell death prognostic risk model ATP1A1 metabolic reprogramming immune microenvironment |
| title | Unveiling ammonia-induced cell death: a new frontier in clear cell renal cell carcinoma prognosis |
| title_full | Unveiling ammonia-induced cell death: a new frontier in clear cell renal cell carcinoma prognosis |
| title_fullStr | Unveiling ammonia-induced cell death: a new frontier in clear cell renal cell carcinoma prognosis |
| title_full_unstemmed | Unveiling ammonia-induced cell death: a new frontier in clear cell renal cell carcinoma prognosis |
| title_short | Unveiling ammonia-induced cell death: a new frontier in clear cell renal cell carcinoma prognosis |
| title_sort | unveiling ammonia induced cell death a new frontier in clear cell renal cell carcinoma prognosis |
| topic | clear cell renal cell carcinoma ammonia-induced cell death prognostic risk model ATP1A1 metabolic reprogramming immune microenvironment |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1636977/full |
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