FABP2 Suppresses Colon Cancer Liver Metastasis by Promoting Ferroptosis Sensitivity
A study finds that FABP2 suppresses colon cancer liver metastasis by increasing ferroptosis sensitivity via β-catenin/GPX4 pathway regulation. Low FABP2 expression correlates with poor survival in advanced colon cancer.
Researchers have identified fatty acid-binding protein 2 (FABP2) as a key regulator that suppresses liver metastasis in colon cancer by increasing sensitivity to ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation. The study reveals that FABP2 interacts with β-catenin to reduce the transcription of glutathione peroxidase 4 (GPX4), a critical enzyme that protects cells against ferroptosis.
Multi-omics analyses of clinical specimens showed that FABP2 expression is reduced in advanced colon cancer, and this reduction is associated with metastatic progression and poor patient survival. Mechanistically, FABP2 binds to β-catenin and alters its intracellular localization, leading to decreased β-catenin/TCF4-dependent transcription of GPX4. This downregulation of GPX4 renders cancer cells more susceptible to ferroptosis.
Overexpression of FABP2 increased ferroptosis sensitivity, whereas downregulation of FABP2 promoted GPX4-dependent evasion of ferroptosis and enhanced metastatic phenotypes. Pharmacological inhibition of Wnt/β-catenin signaling or GPX4 activity partially attenuated the effects of FABP2 loss, confirming the pathway’s involvement.
The findings position FABP2 as a factor associated with ferroptosis regulation and metastatic progression in colon cancer, providing additional insight into the interplay between lipid metabolism, Wnt/β-catenin signaling, and ferroptosis.