A Closed Computational–Experimental Loop Identifies Metabolic Collapse at the Root of Macrophage Dysfunction due to Zinc Dyshomeostasis

ABSTRACT Zinc plays a crucial role in immune regulation, the oxidative stress response, and epithelial barrier integrity, yet zinc’s precise role in regulating metabolic and immunological functions in myeloid cells remains poorly understood. Here, we employ a systems biology approach using constraint-based modeling to elucidate the consequences of myeloid-specific loss of ZIP8 on macrophage metabolic function and antibacterial capabilities. We demonstrate that macrophage populations in the lung of ZIP8 knockout ( Zip8 KO) mice exhibit widespread metabolic disruption, spanning glycolysis, butanoate metabolism, amino acid metabolism, and mitochondrial function. Specifically, Zip8 KO macrophages exhibit impaired nutrient uptake and dysregulated energy metabolism, which is exacerbated following Streptococcus pneumoniae infection. Genome-scale metabolic modeling and flux analysis revealed a paradoxical pattern of metabolic suppression prior to infection, followed by overcompensation post-infection, potentially driving immune dysfunction. Consistent with these predictions Zip8 KO bone marrow-derived macrophages displayed increased ATP demand and disrupted mitochondrial energetics, compromising their ability to control infection. Importantly, we identified succinate, and kynurenic acid as metabolites capable of restoring immune responses and validated their ability to enhance bacterial clearance in Zip8 KO BMDMs. Together, these findings establish ZIP8 as a central regulator of immune-metabolic homeostasis and suggest potential therapeutic avenues to restore immune function in settings of zinc deficiency.