Yuankai Yan

Gram-negative bacteria pose a significant threat to global health due to their high prevalence, multidrug resistance, and association with various infections. Zinc, an essential trace element, plays a dual role in host–microbe interactions, being crucial for both host immune function and bacterial metabolism. Maintaining optimal zinc homeostasis is essential for effective host defense and microbial survival. We comprehensively examine the multifaceted roles of zinc in host–microbe interactions, particularly focusing on its implications for the pathogenicity of Gram-negative bacteria and host immunity. As part of nutritional immunity, hosts have evolved zinc-mediated antimicrobial strategies that manipulate metal availability at the host–pathogen interface, including zinc limitation that restricts bacterial access to this essential nutrient and zinc intoxication that exposes invading bacteria to cytotoxic zinc concentrations. In Gram-negative bacteria, zinc homeostasis, maintained through zinc transporters and efflux systems, critically governs bacterial virulence, biofilm formation, and survival under host-imposed nutritional immunity. By integrating current advances, this review highlights zinc homeostasis as a central determinant of host–pathogen interactions and a promising target for combating multidrug-resistant Gram-negative infections. Understanding these complex zinc-mediated mechanisms provides new perspectives for developing metal-targeted therapeutic strategies.