Patients with high concurrent expression of all three proteins had significantly shorter overall survival and disease-free survival, indicating that the USP21–HSP90–HIF1A/ENO1 axis is not only involved in metabolic reprogramming but also holds potential prognostic value, offering new molecular markers and intervention targets for the metabolic targeted therapy of cholangiocarcinoma. This evidence concerns the gene HIF1A and cholangiocarcinoma.