Iron, Biofilm, and Colorectal Cancer: Mechanistic Insights Into Enterococcus faecalis Pathogenesis

ABSTRACT Enterococcus faecalis is a commensal of the human gastrointestinal microbiota that has emerged as a successful opportunistic pathogen associated with persistent infections, antimicrobial resistance, and biofilm formation. Increasing evidence indicates that iron availability functions as a master environmental signal coordinating E. faecalis pathogenic traits. This review summarizes clinical, molecular, and sequencing‐based studies linking iron homeostasis to extracellular DNA (eDNA) dynamics, biofilm architecture, virulence regulation, and immune evasion, and critically evaluates the emerging but still associative evidence connecting E. faecalis to colorectal carcinogenesis. We highlight how iron sensing and uptake systems modulate biofilm stability through eDNA release, metabolic cooperation, and transcriptional control via the ferric uptake regulator (Fur) and other regulatory networks. We further integrate experimental findings that suggest how these mechanisms may promote inflammation‐driven tumorigenesis in the colon, although a complete causal pathway has not yet been established. Finally, we discuss translational implications, including iron‐targeting and eDNA‐disruptive strategies as promising anti‐virulence approaches, and identify key knowledge gaps requiring future investigation. This review positions iron metabolism at the center of E. faecalis pathogenicity and underscores its potential as a therapeutic target, while recognizing the need for further mechanistic and clinical validation.