CFHR5 promotes colorectal cancer by upregulating COX4I2 to inhibit ferroptosis

Background: Colorectal cancer (CRC) remains one of the most common gastrointestinal malignancies worldwide, characterized by high incidence and mortality rates. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a critical mechanism in tumor biology. However, the regulatory role of CFHR5 (Complement Factor H-Related Protein 5) in ferroptosis and CRC progression remains unclear. Methods: We applied Mendelian randomization (MR) to evaluate the causal role of CFHR5 in CRC. Mediation MR was further employed to assess ferroptosis-related genes as potential mediators. Differential expression and correlation analyses were conducted using multiple CRC transcriptomic cohorts. Functional enrichment and Gene Set Variation Analysis (GSVA) were performed to investigate ferroptosis-related pathways. In addition, drug sensitivity prediction and molecular docking were carried out to identify potential therapeutic targets. Results: MR analysis demonstrated a significant positive association between CFHR5 expression and CRC risk (FinnGen: OR = 1.233, P = 0.004; UK Biobank: OR = 1.072, P < 0.001). Mediation MR identified COX4I2 as a key ferroptosis-related mediator, accounting for 16.4% and 21.8% of the total effect in Finnish and UK cohorts, respectively. Transcriptomic validation confirmed elevated CFHR5 and COX4I2 expression in CRC tissues, with a strong positive correlation between them. Enrichment analyses indicated that CFHR5-related genes were significantly involved in cholesterol metabolism, iron binding, and oxidative stress pathways. GSVA showed that CFHR5 expression was negatively correlated with ferroptosis-related pathways. Drug sensitivity analysis suggested that CFHR5 downregulation increased CRC cell sensitivity to ABT-737, while molecular docking revealed a strong binding affinity between CFHR5 and ABT-737 (binding energy: −9.4 kcal/mol). Conclusions: Our study demonstrates that CFHR5 promotes CRC progression by upregulating COX4I2 and inhibiting ferroptosis. These findings highlight CFHR5 as a promising biomarker and therapeutic target for CRC, warranting further validation in experimental and preclinical models.