CFHR5 promotes colorectal cancer by upregulating COX4I2 to inhibit ferroptosis

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.

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.

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).

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.