Endoplasmic Reticulum Stress Promotes Colorectal Cancer Proliferation by Regulating Autophagy via XBP1s

Background: X-box binding protein 1 spliced (XBP1s), a key downstream molecule of endoplasmic reticulum stress (ERS), is widely involved in processes such as proliferation, invasion, and apoptosis in cancer. However, the role and underlying mechanism of XBP1s in colorectal cancer (CRC) remain poorly understood. We hypothesize that XBP1s plays a critical role in promoting CRC proliferation through the regulation of autophagy. Methods: Based on The Cancer Genome Atlas (TCGA) database, the expression of XBP1 in pan-cancer tissues and CRC tissues was analyzed. Western blotting (WB) and immunohistochemistry (IHC) were used to validate the protein expression level of XBP1s in clinical CRC tissues, and its correlation with clinicopathological characteristics and patient prognosis was assessed. The effects of XBP1s on CRC cells were examined using ex vivo cell experiments. Furthermore, bioinformatic analyses, including Gene Ontology (GO) functional annotation and Gene Set Enrichment Analysis (GSEA) pathway enrichment, were employed to predict downstream pathways associated with XBP1s, which were subsequently validated through follow-up experiments. Results: The expression of XBP1s was significantly higher in CRC tissues compared to normal tissues and was significantly associated with poor prognosis in CRC patients. Knockdown of XBP1s expression ex vivo markedly inhibited CRC cell proliferation and promoted apoptosis. GO and GSEA enrichment analyses revealed a close association between XBP1 and the autophagy signaling pathway. Consequently, by utilizing inhibitors and establishing an endoplasmic reticulum stress model, it was demonstrated that XBP1s might promote CRC growth and proliferation by activating autophagy. Conclusion:Our findings indicate that interference with XBP1s expression can inhibit the malignant proliferation of CRC by suppressing the autophagy signaling pathway. Targeting XBP1s may represent a novel therapeutic strategy for the diagnosis and treatment of CRC patients.