Loss of Farnesoid X Receptor promotes colorectal liver metastasis via the GutFXR–FGF15–PPARγ–VEGFα–MDSC axis
- 1Department of Oncology, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215000 China
- 2Department of General Surgery, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, Suzhou, 215000 China
- 3Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, 215000 China
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Graphical Abstract:
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s10020-026-01600-7.
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BibTeX
@article{chen2026loss,
title = {{Loss of Farnesoid X Receptor promotes colorectal liver metastasis via the GutFXR–FGF15–PPARγ–VEGFα–MDSC axis}},
author = {Yan Chen and Yufei Wu and Yu Yang and Yi Lu and Feng Guo and Xiaofei Qi},
journal = {Molecular Medicine},
year = {2026},
month = aug,
doi = {10.1186/s10020-026-01600-7},
url = {https://doi.org/10.1186/s10020-026-01600-7},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Loss of Farnesoid X Receptor promotes colorectal liver metastasis via the GutFXR–FGF15–PPARγ–VEGFα–MDSC axis
AU - Yan Chen
AU - Yufei Wu
AU - Yu Yang
AU - Yi Lu
AU - Feng Guo
AU - Xiaofei Qi
PY - 2026
DA - 2026/08/08
JO - Molecular Medicine
DO - 10.1186/s10020-026-01600-7
UR - https://doi.org/10.1186/s10020-026-01600-7
AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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. Graphical Abstract: Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s10020-026-01600-7.
SN - 1076-1551
SN - 1528-3658
ER -