IFFO1 (intermediate filament family orphan 1) is a nuclear matrix protein that plays a critical role in maintaining genomic stability by preventing chromosome 12 during DNA double-strand break (DSB) repair 1. The protein functions as a key component of the non-homologous end joining (NHEJ) pathway, forming a heterotetramer with XRCC4 and being recruited to DSB sites in an XRCC4-dependent manner 1. IFFO1's primary mechanism involves interacting with nuclear lamina component LMNA to form an interior nucleoskeleton that immobilizes broken DNA ends, thereby preventing aberrant chromosome 12 1. This nucleoskeleton network, composed of IFFO1-IFFO2-Lamin A/C, has dual functions in promoting end-joining repair and suppressing chromosome 12 2. IFFO1 demonstrates significant disease relevance as a tumor suppressor, with downregulation observed across multiple cancer types including ovarian and lung cancers 34. In ovarian cancer, IFFO1 inhibits β-catenin nuclear translocation, reducing metastasis and cisplatin resistance 3. The protein also regulates lung cancer cell migration by inhibiting IQGAP3-Cdc42 interactions 4. Clinically, IFFO1 promoter methylation serves as a potential blood-based biomarker for ovarian cancer detection 5, and rare variants associate with Alzheimer's disease biomarkers related to neuronal injury and inflammation 6.