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CALR mutation is a key driver of myeloproliferative neoplasms (MPN) and has become a critical biomarker in clinical diagnostics and therapy. However, its function and mechanisms in solid tumors, particularly bladder cancer (BLCA), remain unclear. This study demonstrates that CALR expression is significantly elevated in BLCA, closely associated with poor patient prognosis, and serves as a critical factor promoting tumor progression. Further investigation reveals that the high expression of CALR stems from a novel positive feedback loop with HIF-1α in the tumor microenvironment: CALR stabilizes HIF-1α protein by von Hippel-Lindau (VHL), while HIF-1α transcriptionally upregulates CALR expression, thereby self-sustaining its high expression levels in BLCA. Mechanistically, CALR promotes the epithelial-mesenchymal transition (EMT) process by inducing intracellular reactive oxygen species (ROS) accumulation and activating the AKT signaling pathway, ultimately driving EMT-associated tumor progression. Finally, we identify the natural small-molecule compound-Sinapine as a direct inhibitor of CALR for the first time. Both in vitro and in vivo experiments confirmed that targeted inhibition of CALR effectively suppresses BLCA growth. This study not only elucidates the mechanism by which CALR maintains high expression through the CALR/HIF-1α positive feedback loop and promotes malignant progression in BLCA but also provides a theoretical foundation for its potential use as a prognostic biomarker and therapeutic target.