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

Year: 2026

Type: article

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.

Source: Molecular Carcinogenesis

DOI: 10.1002/mc.70143

Authors: Zheng Ge, Wei Guo, Jingxin Li, Yanqing Wang, Kexin Wang

Institutions: Qilu Hospital of Shandong University, Shandong University

Language: English

Topic: Ferroptosis and cancer prognosis

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: Shandong University, National Natural Science Foundation of China