Computational characterization of three conserved pathogenicity-associated genomic regions in Fusobacterium nucleatum ATCC 25586

Abstract Fusobacterium nucleatum is a Gram-negative anaerobic oral bacterium associated with colorectal cancer progression and adverse clinical outcomes, but the genomic basis of its pathogenicity remains incompletely understood. We applied an integrative computational analysis of the ATCC 25586 genome combining genomic island prediction, genome annotation, comparative genomics, virulence-factor analysis, protein interaction networks, protein structure prediction, gene-expression analysis, and genome-scale metabolic modelling. Three genomic regions containing genes associated with haemolysin production, metabolic adaptation, toxin–antitoxin systems, colonization, and immune evasion were identified. Comparative analysis of 15 Fusobacterium genomes suggests that these regions are broadly conserved and vertically inherited. Metabolic modelling predicted complete growth arrest under iron deprivation and a 28.5% reduction in predicted growth under low-iron conditions. Co-expression and gene-expression analyses identified coordinated activity within these regions, including induction of glycogen-metabolism genes during stationary phase. Based on the convergence of computational evidence and published literature, we propose a Hemolysin–Iron–ROS–Hippo pathway as a testable mechanistic hypothesis for F. nucleatum’s contribution to colorectal cancer progression. All findings are computational predictions requiring experimental validation.