Colorectal cancer (CRC) is one of the most common malignant tumors. Isoliquiritigenin (ISL), a natural chalcone compound extracted from the roots of licorice and other plants, has shown significant antitumor activity in various cancers. However, its specific mechanism of action against CRC remains unclear. Here, researchers explored the molecular mechanism by which ISL targets fibroblast growth factor receptor 4 (FGFR4) in CRC. The study found that FGFR4 is highly expressed in CRC cell lines, and functional experiments showed that silencing FGFR4 significantly inhibited cell proliferation and migration. Further mechanistic studies revealed that FGFR4 regulates fatty acid biosynthesis and the PI3K/Akt signaling pathway, as confirmed by the downregulation of fatty acid synthase (FASN) and PI3K/Akt pathway proteins after FGFR4 knockdown. Furthermore, ISL significantly inhibited CRC cell proliferation and migration while interfering with fatty acid metabolism in tumor cells. This study suggests that ISL may inhibit CRC progression by downregulating FGFR4 and inhibiting PI3K/Akt-mediated fatty acid metabolism reprogramming.
To investigate downstream effector proteins of FGFR4, researchers compared genes downregulated in FGFR4 knockdown cells with differentially expressed genes between high and low FGFR4 expression groups in the TCGA-COAD dataset, and further compared these genes with those related to fatty acid biosynthesis. The results showed that fatty acid synthase (FASN) was the only overlapping gene (Figure 1A). TCGA-COAD database analysis indicated a positive correlation between FGFR4 and FASN expression levels (Figure 1B). qRT-PCR and Western blot analyses showed that FASN expression levels were decreased in both FGFR4 knockdown SW480 and SW620 cells (Figures 1C-D). Furthermore, treatment of SW480 cells with the FGFR4-specific inhibitor robrutinib reduced PI3K and Akt phosphorylation levels, as well as FABP5 expression (Figure 4E). These findings suggest that FGFR4 promotes fatty acid metabolism remodeling by activating the downstream PI3K-Akt pathway and upregulating FASN expression, thereby contributing to the occurrence and development of colorectal cancer.
Figure 1. FGFR4 promotes fatty acid metabolism in colorectal cancer by upregulating FASN. (Zhai X, et al., 2025)