GCH1, identified by a ferroptosis-related prognostic model, contributes to progression and drug resistance of esophageal cancer.
OBJECTIVE: Esophageal cancer has a poor prognosis and limited treatment options. Ferroptosis, an iron-dependent cell death pathway, is a promising therapeutic target; however, its significance in esophageal cancer remains largely unexplored. Here, we investigated the prognostic significance of ferroptosis-related genes in esophageal cancer and identified a key functional regulator that may serve as a therapeutic target. METHODS: We analyzed ferroptosis-related gene expression profiles with The Cancer Genome Atlas-Esophageal Carcinoma (TCGA-ESCA) cohort and constructed a prognostic risk model using LASSO Cox regression analysis. Among the genes in this model, GTP cyclohydrolase 1 (GCH1) was selected for functional investigation, based on its established role in antioxidant defense. Subsequently, in vitro experiments were performed to assess the effects of GCH1 knockdown on cell proliferation, migration, clonogenicity, and ferroptosis-related biochemical indicators. The role of GCH1 in antitumor immunity was evaluated through co-culture of esophageal cancer cells with activated T cells, and drug sensitivity was assessed using cytotoxicity assays. RESULTS: A prognostic model consisting of nine ferroptosis-related genes (STC2, TRIB3, HMGB3, CXCL8, GCH1, PARP10, APOE, MTIM, and GPER1) with reliable risk stratification was constructed. The prognostic model could reflect the differences in drug responses and immune cell infiltration. GCH1 knockdown suppressed esophageal cancer cell proliferation, migration, and clonogenicity. Furthermore, GCH1 knockdown increased the intracellular levels of reactive oxygen species, lipid peroxidation, and ferrous iron (Fe2+). Co-culture assays demonstrated that GCH1 knockdown in tumor cells increased the production of granzyme B and interferon-γ by CD8+ T cells. Moreover, GCH1 silencing sensitized esophageal cancer cells to both sorafenib and cisplatin. CONCLUSIONS: This study established a ferroptosis-related prognostic model for esophageal cancer and identified GCH1 as a critical regulator that contributes to esophageal cancer progression and drug resistance. These findings suggest that targeting GCH1 may be a promising strategy to improve drug sensitivity and clinical outcomes in esophageal cancer.