Zinc, an essential micronutrient for antiviral immunity and redox balance, has long been linked to COVID-19 outcomes, low serum zinc levels are associated with worse prognosis. However, the intracellular mediators that translate systemic zinc status into immune dysregulation and disease severity remain unclear, creating a critical gap in developing precise host-directed therapies for COVID-19.
To address this gap, a research team led by Professor Bo Zhu from China Pharmaceutical University, in collaboration with researchers from King's College London, combined clinical evidence and multi-omics analyses to explore zinc-related host factors in COVID-19. The study, published online on February 13, 2026, in Targetome, identified MT2A (metallothionein 2A) as a pivotal node connecting zinc dysregulation to COVID-19 mortality.
First, the team conducted a PRISMA-guided meta-analysis of seven studies involving 1,972 hospitalized COVID-19 patients, comparing outcomes between those who received zinc supplements and those who received placebo or standard care. The results showed that zinc supplementation significantly reduced in-hospital mortality, with a pooled odds ratio (OR) of 0.48 (95% confidence interval [CI]: 0.36–0.64). Sensitivity analyses confirmed the robustness of this finding, with low statistical heterogeneity across studies, despite variations in zinc formulation, dose, route, and treatment duration.
To uncover the intracellular mechanisms linking zinc to COVID-19 severity, the researchers integrated single-cell and bulk transcriptomic data across multiple tissue compartments, peripheral blood mononuclear cells (PBMCs), bronchoalveolar lavage fluid (BALF), sputum, and postmortem lung tissue. Using a large single-cell atlas (GSE158055) containing 1,462,702 cells from 196 individuals, as well as bulk RNA-seq datasets from postmortem lung tissue (GSE183533) and longitudinal peripheral blood (GSE198449), they found that MT2A exhibited the most consistent association with disease severity among metallothioneins.

MT2A, a cysteine-rich protein that acts as a dynamic zinc reservoir and redox regulator, was enriched in myeloid lineages (monocytes and macrophages). Its expression was compartment- and state-dependent: in PBMCs, MT2A expression was lower in mild/moderate COVID-19 cases but significantly higher in severe/critical cases. In BALF and sputum samples, MT2A expression varied by cell type, correlating positively with SARS-CoV-2-related genes such as CTSB, CTSL, and IFIH1, key players in viral entry, processing, and innate immune sensing.
In postmortem lung tissue from COVID-19 decedents, MT2A expression was significantly higher than in healthy controls, and it was positively correlated with viral entry factors TMPRSS2 and CTSL, while negatively correlated with inflammatory cytokines IL10 and IL18. Using STRING software, a tool for constructing protein-protein interaction (PPI) networks, the team identified a MT2A-centered PPI network involving other metallothioneins, STAT1, and EOLA1, suggesting potential connections to interferon signaling and inflammatory regulation.
Longitudinal analysis of peripheral blood from nine patients with complete timepoints (days 0, 1, 8, and 12 post-infection) revealed that MT2A expression peaked at day 1 after infection and declined thereafter, consistent with an inducible acute-phase response. Its expression trajectory was highly consistent with genes involved in viral sensing and inflammation, such as CTSL, TLR7, and IFIH1, highlighting its role in the early inflammatory phase of COVID-19.
“MT2A is not just a passive responder to zinc status, but a key integration point linking inflammation, redox stress, and zinc metabolism,” said Professor Bo Zhu, corresponding author of the study. “Our findings suggest that MT2A can serve as a cross-compartment biomarker for metal/redox immune stress, helping to stratify patients and guide the timing of zinc or host-directed interventions.”
While the study highlights MT2A as a candidate host target, the researchers note that further perturbation-based studies are needed to validate its causal role. Additionally, the heterogeneous zinc regimens in the meta-analysis underscore the need for standardized protocols in future clinical trials. Nevertheless, the findings provide a rationale for developing biomarker-stratified strategies to improve COVID-19 treatment outcomes.
This work entitled “Multi-omics integration identifies MT2A as a biomarker and a candidate host target linking zinc dysregulation to COVID-19 mortality” was published online 13 February, 2026, in Targetome.

DOI：10.48130/targetome-0026-0006