Colorectal Cancer Liver Metastasis‐Associated Ferroptosis‐Related Genes Modulate Lipid Peroxidation in Colorectal Cancer Cells

ABSTRACT Distant metastasis, predominantly to the liver, remains the leading cause of death in colorectal cancer (CRC), yet biomarkers that capture metastatic competence remain limited. Ferroptosis is an iron‐dependent, lipid peroxidation‐driven form of regulated cell death that can restrain tumor progression, but whether primary CRC from patients with liver metastasis shows ferroptosis‐resistance‐related features remains incompletely understood. In a small exploratory set of T‐stage‐matched primary CRC tumors with or without liver metastasis, we quantified glutathione redox and lipid peroxidation‐related readouts and assessed SLC7A11 and GPX4 expression. We integrated GSE62321 transcriptomic profiles with a FerrDb ferroptosis gene set, evaluated prognosis in TCGA‐COAD/READ, and performed genetic knockdown, MDA assays, C11‐BODIPY lipid ROS staining, ferrostatin‐1 rescue assays, and Transwell assays in CRC cell models. Primary tumors from patients with liver metastasis showed a more reduced redox profile and increased expression of core ferroptosis‐suppressive proteins, consistent with enhanced ferroptosis resistance potential but not direct evidence of lower in vivo ferroptotic cell death. Integrative discovery highlighted fatty acid binding protein 4 (FABP4), α‐synuclein (SNCA), and discoidin domain receptor 2 (DDR2) as CRC‐LM‐associated ferroptosis‐related candidates. High expression of each gene was associated with unfavorable disease‐free survival. In CRC cell models, including the lymph‐node‐metastasis‐derived SW620 line and additional validation lines, silencing FABP4, SNCA, or DDR2 increased bulk MDA and/or C11‐BODIPY‐detected lipid ROS, altered ferroptosis susceptibility, and suppressed migratory and/or invasive phenotypes. Ferrostatin‐1 partially rescued knockdown‐induced viability loss, lipid ROS accumulation, and migratory/invasive defects, supporting involvement of ferroptosis‐associated lipid peroxidation while not excluding broader stress‐response mechanisms. FABP4, SNCA, and DDR2 are CRC‐LM‐associated ferroptosis‐related candidates that modulate lipid peroxidation, ferroptosis susceptibility, and migratory/invasive phenotypes in CRC cell models, warranting further validation in viability‐controlled and liver metastasis‐specific models.