AIF1L as a Ferroptosis-Linked Biomarker in Microsatellite States-Driven Colorectal Cancer: Functional and Diagnostic Insights From Multiomics Analysis.

BACKGROUND: Microsatellite instability (MSI) serves as a crucial biomarker for immune checkpoint blockade therapy in colorectal cancer (CRC). However, only around 40% of MSI CRC patients benefit from ICB. Investigating the mechanisms underlying MSI CRC, particularly its association with cell death and the immune microenvironment, can provide insights to improve immunotherapy efficacy. METHODS: Transcriptomic and clinical data of MSI CRC patients were collected from TCGA and GEO databases. Differential expression analysis, weighted gene coexpression network analysis, and Cox regression models were employed to identify five cell death-related prognostic genes (POU4F1, AIF1L, SLC18A1, INSL4, and HOXC6). Single-cell analysis, immune infiltration analysis, and in vitro and in vivo experiments were conducted to validate their roles in MSI CRC. RESULTS: The five-gene risk model effectively stratified high- and low-risk groups and predicted survival differences (AUC > 0.6). AIF1L exhibited elevated expression in MSI-H groups and demonstrated a significant correlation with ferroptosis and immune cell infiltration. In vitro experiments showed that AIF1L boosted cell proliferation and migration via modulating ferroptosis, showing correspondence with in vivo experiments. Moreover, enrichment analysis revealed that AIF1L participated in immune-related signaling pathways, potentially impacting the tumor microenvironment and patient prognosis. CONCLUSION: AIF1L may regulate MSI CRC progression by promoting ferroptosis, serving as a prospective biomarker for prognosis and a therapeutic target for personalized therapy. This study uncovers new mechanisms in MSI CRC and provides a foundation for optimizing immunotherapy, though further investigation into its specific roles is needed.