Fatty acid-binding protein 2 suppresses liver metastasis by cytoplasmic sequestration of β-catenin to enhance ferroptosis sensitivity in colon cancer

Abstract Metastatic colon cancer commonly exhibits resistance to ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation. However, the mechanisms linking metabolic regulation to ferroptosis during metastatic progression remain incompletely understood. Here, we identified fatty acid-binding protein 2 (FABP2) as a regulator associated with ferroptosis sensitivity and liver metastatic phenotypes in colon cancer. Multi-omics analyses of clinical specimens showed reduced FABP2 expression in advanced colon cancer, which was associated with metastatic progression and poor survival. Mechanistically, FABP2 interacted with β-catenin, altered its intracellular localization, and was associated with reduced β-catenin/TCF4-dependent transcription of glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis resistance. FABP2 overexpression increased ferroptosis sensitivity, whereas FABP2 downregulation promoted GPX4-dependent ferroptosis evasion and metastatic phenotypes. Pharmacological inhibition of Wnt/β-catenin signaling or GPX4 activity partially attenuated the effects of FABP2 loss. Together, these findings identify FABP2 as a factor associated with ferroptosis regulation and metastatic progression in colon cancer, and provide additional insight into the interplay between lipid metabolism, Wnt/β-catenin signaling, and ferroptosis.