Zinc homeostasis plays a crucial role in host defense against infection and disease pathogenesis due to its involvement in immune regulation, oxidative stress response, epithelial barrier integrity, and cellular metabolism. Dysregulated zinc levels are associated with various pathological conditions, including bacterial infections, chronic obstructive pulmonary disease (COPD), and lung cancer. Systematic approaches that integrate “omics” technologies, computational modeling, and network analyses provide a powerful framework for understanding the complex interplay between zinc dynamics and immune function under stress conditions. In this study, we investigated the role of ZIP8, a critical zinc transporter essential for immune homeostasis, in metabolic and immune responses during Streptococcus pneumoniae infection. Our findings demonstrate that ZIP8 knockout significantly disrupts metabolic processes, particularly butanoate metabolism, and amino acid pathways, leading to mitochondrial dysfunction and impaired nutrient uptake. ZIP8-deficient mice exhibited an overcompensatory metabolic response, exacerbating these deficiencies following infection and further impairing immune function.
