CAV1 Stabilizes EPAS1 via VHL in Colon Cancer to Promote Autophagy‐Dependent Ferroptosis, Inhibits Stemness and Improves Anti‐ PD ‐1 Efficacy

ABSTRACT Colorectal cancer (CRC) is one of the most common malignant tumors in the digestive system. Immune checkpoint blockade (ICB) is a promising strategy for CRC treatment, but its limited efficacy poses a challenge. Bioinformatics methods were used to screen ferroptosis‐related genes in CRC. Cellular biology methods investigated endothelial PAS domain protein 1 (EPAS1) impact on cellular characteristics, stemness, and ferroptosis. Finally, in vivo experiments validated EPAS1's influence on anti‐PD‐1 therapy efficacy. We have found that EPAS1 is a risk gene in CRC, which can inhibit the growth, invasion, and stemness of colon cancer cells both in vitro and in vivo, and promote ferroptosis. Mechanistically, caveolin 1 (CAV1) regulates the expression of von Hippel–Lindau tumor suppressor (VHL) to inhibit the ubiquitination of EPAS1, increase its stability, further enhance the expression of nuclear receptor coactivator 4 (NCOA4) and autophagy‐lysosome formation, leading to cell iron overload and inducing ferroptosis. Our study confirms EPAS1 regulates ferroptosis, impacting epithelial–mesenchymal transition (EMT) and stemness in CRC cells, and highlights its role in ICB. These findings inform CRC treatment.