IFFO1, also known as Intermediate filament family orphan 1, is a non-homologous end-joining protein. It structurally forms a heterotetramer with XRCC4 and is recruited to DNA damage sites by XRCC4, promoting the repair of DNA double-strand breaks in a parallel pathway with XLF. IFFO1 also interacts with lamin A/C to form an interior nucleoskeleton, playing a crucial role in maintaining genome integrity [2,3].

In ovarian cancer, IFFO1 is downregulated at both transcriptional and post-transcriptional levels. Transcriptionally, HDAC5 recruited by the transcription factor YY1 inhibits its expression, and post-transcriptionally, the METTL3/YTHDF2 axis regulates its mRNA stability in an m6A-dependent manner. Overexpression of IFFO1 in ovarian cancer cells inhibits the translocation of β-catenin to the nucleus, decreasing tumor metastasis and cisplatin resistance. Mice injected with IFFO1-overexpressing cells had lower ascites volumes and tumor weights in the peritoneal cavity compared to control-injected mice, indicating its role as a tumor suppressor [1]. Also, in ovarian cancer, methylation of the IFFO1 promoter (IFFO1-M) is frequently detected in tumors and rarely in normal controls, suggesting its potential as a blood-based biomarker for ovarian cancer detection [4]. High levels of cell-free tumour-derived DNA (ctDNA) with methylated IFFO1 promoter in ascites are associated with a shorter paracentesis-free interval, and ctDNA presence in plasma is unfavorable for survival [5].

In conclusion, IFFO1 is essential for DNA double-strand break repair and maintaining genome integrity. In ovarian cancer, model-based research, especially overexpression in mice, has revealed its role as a tumor suppressor. Its downregulation mechanisms and potential as a biomarker highlight its significance in understanding and treating ovarian cancer.