The ESX-3 secretion system serves as a core component in maintaining metal ion homeostasis in mycobacteria, playing an indispensable role in the acquisition of essential elements such as iron and zinc. As a critical virulence determinant, its functional scope extends to immune modulation, cell wall integrity, and antibiotic resistance. This review synthesizes current knowledge on the genetic architecture, evolutionary trajectory, and structural composition of ESX-3, revealing its complex evolutionary history involving both vertical inheritance and horizontal gene transfer via plasmids. We explore its multifaceted biological functions in pathogenesis and its emerging link to antibiotic susceptibility. We also detail its sophisticated regulatory network, governed by metal-dependent transcription factors (IdeR, Zur, MntR), toxin-antitoxin systems, and oxidative stress pathways. Furthermore, we explore its multifaceted biological functions in pathogenesis and its emerging, complex link to antibiotic susceptibility. By integrating existing literature with our preliminary findings, this work provides a comprehensive overview of ESX-3, highlighting its potential as a novel therapeutic target and outlining future research directions to unravel its full functional and mechanistic spectrum. • Reveals dual evolutionary paths of ESX-3: vertical inheritance and horizontal transfer. • First systematic characterization of ESX-3 subcluster differentiation. • Delves into the complex role of ESX-3 in virulence, drug resistance, and its therapeutic potential.
Wang et al. (Sun,) studied this question.