Multi omics landscape of AGTRAP in ammonia induced cell death and cervical cancer progression

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Abstract Background Cervical cancer (CESC) remains a leading cause of cancer-related mortality among women worldwide. Ammonia‑induced cell death, a recently identified metabolic cell death process, plays a significant yet incompletely understood role in tumor progression. Its regulatory mechanisms and clinical relevance in cervical carcinogenesis are poorly defined. This study aimed to elucidate the function of ammonia‑induced cell death in CESC and to identify its pivotal regulatory molecules. Methods Multi-omics data from the TCGA-CESC cohort were integrated. Differential expression analysis combined with an ensemble machine-learning algorithm was employed to identify core ammonia‑induced cell death-related genes. Cellular and spatial heterogeneity of gene expression were dissected using single-cell RNA sequencing (GSE168652) and spatial transcriptomics. Intercellular communication networks were deciphered via CellChat analysis. Drug sensitivity was assessed using the GDSC and CTRP databases. Functional validation was performed through AGTRAP overexpression and knockdown experiments in SW756 and SiHa cell lines. Results Pathway activity analysis revealed a significant suppression of ammonia‑induced cell death in cervical tumors. Four core genes were screened, with AGTRAP emerging as the central hub. AGTRAP was specifically upregulated in CESC, served as an independent risk factor for shortened overall survival, and exhibited high diagnostic accuracy (AUC = 0.947). Single-cell and spatial analyses confirmed its predominant enrichment in malignant epithelial cells. Mechanistically, AGTRAP-positive malignant cells functioned as communication hubs within the tumor microenvironment, interacting with macrophages via pathways like SPP1-CD44 and reciprocally shaping an immunosuppressive milieu through secreting factors such as MIF. Functionally, AGTRAP orchestrated mitochondrial metabolism and activated the IL6-JAK-STAT3 inflammatory axis to drive progression. In vitro assays confirmed that AGTRAP promoted proliferation, migration, and invasion of cervical cancer cells. Furthermore, high AGTRAP expression was associated with resistance to chemotherapeutic agents like paclitaxel, while computational drug screening nominated MK-886 as a potential therapeutic candidate. Conclusion This study identifies AGTRAP as a key biomarker that modulates ammonia‑induced cell death, remodels the immune microenvironment, and fuels malignant progression in cervical cancer, providing novel insights for prognosis prediction and therapeutic targeting.