Integrative Transcriptomic and Single‐Cell Analyses Identify ATP1A1 as a Prognostic and Immune‐Associated Factor in Esophageal Cancer

Background Esophageal cancer is a highly aggressive malignancy with poor prognosis and limited molecular markers for effective risk stratification and therapeutic guidance. Mitochondrial stress–related pathways are increasingly recognized as important regulators of tumor progression and immune modulation; however, their clinical relevance in esophageal cancer remains insufficiently characterized. Methods Transcriptomic and clinical data of esophageal cancer were obtained from public databases. A predefined mitochondrial stress–related gene set was analyzed using LASSO Cox regression to construct a prognostic model. Survival analysis, functional enrichment, immune regulatory profiling, and immune cell infiltration analyses were subsequently performed. Single‐cell RNA sequencing data from the GSE160269 cohort were used to localize gene expression within the tumor microenvironment. In addition, pan‐cancer drug sensitivity analyses were conducted using pharmacogenomic datasets. Results ATP1A1 was identified as the only LASSO‐selected gene demonstrating consistent prognostic significance, with higher expression associated with improved survival outcomes. Functional analyses indicated that ATP1A1 expression was mainly associated with metabolic pathways and negatively correlated with epithelial–mesenchymal transition, invasion, and quiescence states. Immune analyses showed that ATP1A1 expression was associated with heterogeneous immunomodulatory patterns, differences in immune cell infiltration, and reduced activity across several steps of the cancer immunity cycle. Single‐cell analysis demonstrated that ATP1A1 expression was not only preferentially enriched in malignant epithelial cells but also detectable in stromal and immune cell populations. Drug sensitivity analyses suggested that ATP1A1 expression was associated with differential responses to multiple therapeutic agents. Experimental validation further showed that ATP1A1 knockdown altered tumor cell behavior and increased inflammatory gene expression in esophageal cancer cells. Conclusions ATP1A1 represents a prognostically relevant factor linked to tumor biological characteristics, immune microenvironment features, and therapeutic response heterogeneity in esophageal cancer.