Linarin Suppresses the Progression of Colorectal Cancer by Inhibiting the HIF‐1α/PD‐L1 Axis

Linarin is a natural flavonoid glycoside that has extensive pharmacological activities, such as anti-inflammatory, antioxidant, and anticancer effects. However, the functions of linarin in colorectal cancer have not been fully elucidated. The purpose of our study was to investigate the effect of linarin on colorectal cancer and delineate its potential molecular mechanisms. The malignant behavior of colorectal cancer cells were investigated utilizing colony formation, 5-ethynyl-2'-deoxyuridine, Annexin V/PI double staining, scratch, and transwell assays. The potential mechanism of linarin's anticancer activity was explored using network pharmacology analysis, molecular docking, qRT-PCR, immunohistochemical staining, western blot analysis, immunofluorescence, CHX chase assay, ubiquitination assay, and rescue experiments. In addition, mouse xenograft tumor models were used to confirm the role of linarin in colorectal cancer in vivo. We found that linarin inhibited the proliferative, migratory, and invasive abilities, but enhanced the apoptotic ability of colorectal cancer cells. Moreover, we also discovered that linarin could repress HIF-1α expression and HIF-1α/PD-L1 axis in LoVo and HCT-15 cells. Both HIF-1α and PD-L1 overexpression reversed the effect of linarin on the malignant behavior of colorectal cancer cells. Furthermore, linarin treatment significantly inhibited colorectal cancer tumor growth in vivo. In conclusion, linarin could inhibit the proliferative, migratory, and invasive capacity, but enhance the apoptotic ability in colorectal cancer cells through repressing the HIF-1α/PD-L1 axis.