This study provides a comprehensive assessment of the gene HSPA5 from a pan-cancer perspective using multi-omics data. HSPA5, a key chaperone protein in the endoplasmic reticulum (ER) stress response, is significantly elevated in various common malignancies and is associated with poor prognosis. The study found that high HSPA5 expression is correlated with overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and disease-specific survival (DSS) in multiple cancers, including bladder cancer (BLCA). Immunohistochemistry on tissue microarrays from 100 BLCA patients confirmed that high HSPA5 expression is significantly associated with poor prognosis. Additionally, the study revealed significant differences in HSPA5 methylation and phosphorylation levels between various malignancies and normal tissues. HSPA5 expression was also correlated with the levels of infiltrating cells and immune checkpoint genes, suggesting its role in immune regulation and potential impact on immunotherapy response. The findings highlight the importance of HSPA5 as a prognostic biomarker and a potential therapeutic target in cancer, particularly in bladder cancer.This study provides a comprehensive assessment of the gene HSPA5 from a pan-cancer perspective using multi-omics data. HSPA5, a key chaperone protein in the endoplasmic reticulum (ER) stress response, is significantly elevated in various common malignancies and is associated with poor prognosis. The study found that high HSPA5 expression is correlated with overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and disease-specific survival (DSS) in multiple cancers, including bladder cancer (BLCA). Immunohistochemistry on tissue microarrays from 100 BLCA patients confirmed that high HSPA5 expression is significantly associated with poor prognosis. Additionally, the study revealed significant differences in HSPA5 methylation and phosphorylation levels between various malignancies and normal tissues. HSPA5 expression was also correlated with the levels of infiltrating cells and immune checkpoint genes, suggesting its role in immune regulation and potential impact on immunotherapy response. The findings highlight the importance of HSPA5 as a prognostic biomarker and a potential therapeutic target in cancer, particularly in bladder cancer.