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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\u20101\u03b1 in the tumor microenvironment: CALR stabilizes HIF\u20101\u03b1 protein by von Hippel\u2013Lindau (VHL), while HIF\u20101\u03b1 transcriptionally upregulates CALR expression, thereby self\u2010sustaining its high expression levels in BLCA. Mechanistically, CALR promotes the epithelial\u2010mesenchymal transition (EMT) process by inducing intracellular reactive oxygen species (ROS) accumulation and activating the AKT signaling pathway, ultimately driving EMT\u2010associated tumor progression. Finally, we identify the natural small\u2010molecule compound\u2014Sinapine as a direct inhibitor of CALR for the first time. Both in\u00a0vitro and in\u00a0vivo 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\u20101\u03b1 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.<\/jats:p>","DOI":"10.1111\/cas.70354","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T20:14:07Z","timestamp":1773000847000},"page":"1286-1302","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>CALR<\/scp>\n                    \/\n                    <scp>HIF<\/scp>\n                    \u20101\u03b1 Positive Feedback Loop Drives\n                    <scp>CALR<\/scp>\n                    Upregulation to Promote\n                    <scp>EMT<\/scp>\n                    \u2010Mediated Bladder Cancer Progression via\n                    <scp>ROS<\/scp>\n                    \/\n       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