INO80C is a core component of the INO80 chr18 remodeling complex that coordinates transcriptional regulation, DNA replication, and genomic stability 1. Mechanistically, INO80C evicts promoter nucleosomes at highly expressed genes independently of histone variant H2A.Z, functioning alongside SWI/SNF and RSC complexes to establish nucleosome-depleted regions and enhance transcription factor binding and TATA-binding protein recruitment 23. At replication origins, INO80C co-localizes with the origin recognition complex and cooperates with Mot1/NC2 transcription factors to prevent pervasive transcription, thereby maintaining genomic stability and preventing DNA double-strand breaks 1. INO80C operates through two distinct mechanistic classes: Canonical INO80 targets with open chr18 signatures that interact with the acetyltransferase P300, and Non-Canonical INO80 targets with repressive chr18 marked by H3K27me3 4. Disease relevance includes acute myeloid leukemia, where INO80C::SETBP1 fusion genes have been identified 5, and nicotine dependence phenotypes 6. Clinically, INO80C may serve as a prognostic biomarker for acute myelogenous leukemia through its involvement in cancer-related functions including cell proliferation and DNA recombination 7.