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FUNDC1 drives cholangiocarcinoma progression via RAC1 interaction and ferroptosis suppression
Xuanming Luo1, Min Li1, Yuda Gong1
1Department of Biliary Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Shanghai Xuhui Central Hospital, Fudan University, Shanghai, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, China; Cancer Center, Zhongshan Hospital, Fudan University, China; Biliary Tract Disease Institute, Fudan University, China; Shanghai Engineering Research Center of Biliary Tract Minimal Invasive Surgery and Materials, China.
International Journal of Biological Macromolecules
|July 18, 2025
Summary
FUNDC1 protein is elevated in cholangiocarcinoma (CCA), promoting cancer progression via ferroptosis. Targeting FUNDC1 and RAC1 may offer new therapeutic strategies for this lethal biliary tract cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Cholangiocarcinoma (CCA) is a deadly biliary tract cancer with limited treatment options.
- FUND14 domain-containing protein 1 (FUNDC1) expression is elevated in CCA.
- Mitochondrial dysfunction and ferroptosis are implicated in cancer progression.
Purpose of the Study:
- To investigate the role of FUNDC1 in CCA progression.
- To explore the relationship between FUNDC1, mitochondrial function, and ferroptosis in CCA.
- To identify potential therapeutic targets for CCA.
Main Methods:
- Analysis of FUNDC1 expression in CCA tissues and cell lines.
- Assessment of mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and glutathione (GSH) levels.
- Investigated ferroptosis markers (Gpx4, SLC7A11, NCOA4).
- Studied the interaction between FUNDC1 and RAC1 using immunoprecipitation.
- Evaluated the effect of FUNDC1 and RAC1 knockdown on tumor growth in vivo.
Main Results:
- FUNDC1 expression is significantly higher in CCA than in normal tissues, correlating with poor prognosis.
- FUNDC1 knockdown disrupts mitochondrial membrane potential, increases ROS, and alters ferroptosis markers in CCA cells.
- FUNDC1 interacts with RAC1, and this interaction is crucial for FUNDC1-induced malignant transformation.
- FUNDC1 knockdown induces ferroptosis, while RAC1 knockdown does not, but both reduce tumor volume in vivo.
- FUNDC1 promotes CCA progression via mitochondrial function-dependent ferroptosis.
Conclusions:
- FUNDC1 plays a critical role in promoting CCA progression.
- FUNDC1-induced ferroptosis, mediated by mitochondrial dysfunction and RAC1 interaction, drives CCA malignancy.
- FUNDC1 represents a promising therapeutic target for cholangiocarcinoma treatment.
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