J Nutr Biochem. 2026 May 15:110416. doi: 10.1016/j.jnutbio.2026.110416. Online ahead of print.
ABSTRACT
Zinc deficiency and chronic low‑grade inflammation are prevalent conditions that compromise epithelial integrity and metabolic homeostasis, particularly in ageing populations. Here, we investigated the concentration-dependent effects of Zn treatment on a well-differentiated human epithelial cell model exposed to cytokine-induced inflammatory stress, combining metallomics, transcriptomics, and metabolomics. Exposure to isotopically enriched Zn (125-, 200-, 250-µM 68ZnSO4) increased intracellular Zn availability and promoted MT metal-loading, revealing a functional Zn window with 200 µM achieving optimal Zn-MT stoichiometry (Zn7.4Cu0.4MT). Zinc pre‑exposure also attenuated cytokine‑responsive inflammatory gene networks while maintaining epithelial differentiation markers, indicating a protective transcriptional program that counteracts inflammation‑induced de‑differentiation. Metabolomic profiling showed that Zn partially restored lipid species suppressed by inflammatory stress, including anti‑inflammatory fatty acid derivatives and selected sphingolipids (docosenamide and sphinganine), while modulating broader lipid classes in a dose‑dependent manner. Together, these multi-layered responses demonstrate that Zn modulates epithelial integrity through coordinated remodeling of metal homeostasis, inflammatory signaling, and lipid metabolism. These findings support the concept that Zn status influences epithelial resistance to inflammatory stress through MT‑mediated buffering and lipid pathway regulation, providing mechanistic insight relevant for nutritional strategies in populations at risk of Zn deficiency.
PMID:42142546 | DOI:10.1016/j.jnutbio.2026.110416