RCC1 Domain‐Containing Protein 1 Promotes Colon Cancer Malignant Progression by Activating Autophagy‐Dependent WNT5A Secretion in Cancer‐Associated Fibroblasts

Background: Autophagy plays a dual role in colon cancer, but its mechanisms in tumor‐stroma interactions are unclear. Methods: Using TCGA‐COAD and GSE161277 datasets, we identified autophagy‐related prognostic genes via bioinformatics and machine learning. RCCD1's role was further investigated using single‐cell RNA‐seq and functional coculture assays (fibroblasts/HCT116 cells), validated in clinical samples. Results: RCCD1 was upregulated in colon cancer and cancer‐associated fibroblasts (CAFs), correlating with poor prognosis. In CAFs, RCCD1 activated AMPK/mTOR/ULK1 signaling, enhancing autophagy and driving WNT5A secretion. This activated the Wnt/CaMKII/ERK pathway in tumor cells, promoting EMT, proliferation, and invasion. These effects were reversed by autophagy inhibition or WNT5A neutralization. Conclusion: The RCCD1‐autophagy‐WNT5A axis is a critical mediator of protumorigenic CAF‐tumor cell crosstalk, representing a novel therapeutic target for colon cancer.