Multi-Omics Integration Identifies MT2A as a Biomarker and a Candidate Host Target Linking Zinc Dysregulation to COVID-19 Mortality

Identifying host programs that connect micronutrient biology to COVID-19 immunopathology may enable more precise host-directed strategies. Zinc deficiency is linked to worse outcomes, yet the intracellular mediators that couple metal/redox stress to disease severity remain unclear. We performed a PRISMA-guided meta-analysis of zinc supplementation in hospitalized COVID-19 (7 studies; 1972 participants) and observed reduced mortality (OR 0.48, 95% CI 0.36–0.64). While statistical heterogeneity was low, regimens varied substantially in formulation, elemental dose, route, and duration. We then integrated single-cell and bulk transcriptomes across blood and respiratory compartments to map zinc-homeostasis programs across disease states. In a large single-cell atlas (GSE158055; 1462702 cells from 196 individuals) spanning PBMC, bronchoalveolar lavage fluid, and sputum, and in bulk RNA-seq from postmortem lung tissue (GSE183533) and longitudinal peripheral blood (GSE198449), MT2A showed the most reproducible association with disease severity among metallothioneins and was enriched in myeloid lineages. Its associations were compartment- and state-dependent and involved SARS-CoV-2–relevant entry/processing and innate-sensing programs, including TMPRSS2, CTSB/CTSL, and RNA-sensing pathways. In a longitudinal subset with complete timepoints (n=9; days 0, 1, 8, and 12), MT2A peaked early after infection and declined thereafter, consistent with an inducible acute-phase response. Together, these results prioritize MT2A as a cross-compartment marker of metal/redox immune stress and a testable host node for biomarker-guided stratification and intervention timing, pending perturbation-based causal validation.