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Loss of Farnesoid X Receptor promotes colorectal liver metastasis via the GutFXR–FGF15–PPARγ–VEGFα–MDSC axis
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DOI：10.1186/s10020-026-01600-7.png)
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Abstract
En 中文
Colorectal cancer (CRC) and colorectal liver metastasis (CRLM) posed significant challenges in cancer management. To develop more effective therapies, we investigated the role of Farnesoid X Receptor (FXR, Nr1h4) in the tumor-liver microenvironment, an area with substantial therapeutic potential that had been underexplored. Employing preclinical mouse models of CRLM, we conducted a comprehensive evaluation of FXR expression and its functional significance in modulating the tumor-liver microenvironment. Techniques utilized included histological analysis, single-cell sequencing, immunohistochemistry (IHC), flow cytometry (FCM), and enzyme-linked immunosorbent assay (ELISA). Antibody depletion experiments, as well as the use of inhibitors and antagonists, were conducted to elucidate the mechanisms underlying FXR's role in colorectal cancer liver metastases. Our findings indicated that FXR knockout or treatment with Ursodeoxycholic Acid (UDCA) promoted CRLM. Single-cell sequencing, FCM, and antibody depletion experiments revealed that FXR affected CRLM prognosis by altering the liver microenvironment, with myeloid-derived suppressor cells (MDSCs) identified as the primary cellular mediators in this process. Mechanistically, the gutFXR-FGF15-PPARγ-VEGFα-MDSC axis played a crucial role in MDSC accumulation, thereby promoting liver metastasis of colon cancer. Our study uncovered a novel function of FXR in regulating the liver microenvironment and influencing CRLM progression. Targeting the gutFXR-FGF15-PPARγ-VEGFα-MDSC axis may offer a promising therapeutic strategy for the prevention and treatment of CRLM.
Keywords:
FXR
CRLM
MDSC
FGF15
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