Combination of gene/protein and metabolite multiomics to reveal biomarkers of nickel ion cytotoxicity and the underlying mechanism.

Biomarkers have been applied for toxicity assessment of biomaterials due to their advantages. However, research on biomarkers for biomaterials is still in its early stages. There is a lack of integrated analysis in biomarker research based on multiomics studies. Herein, we report a new approach for combining of gene/protein and metabolite multiomics to reveal biomarkers of nickel ion (Ni²⁺) cytotoxicity and the underlying mechanism. Firstly, differentially expressed genes and proteins were compared to screen gene/protein pairs exhibiting consistent differential expression within the same Ni²⁺-treated groups. Next, metabolic pathway analysis was carried out to reveal pathways in which gene/protein pairs and metabolites showed upstream and downstream relationships. Important networks composed of gene/protein pairs, metabolites and metabolic pathways and candidate biomarkers were subsequently identified. Through expression level and function validation, the gene/protein/metabolite biomarkers were confirmed, and the underlying mechanism was revealed: Ni²⁺ influenced the expression of the Rrm2 gene biomarker, which subsequently affected the expression of the RRM2 protein biomarker. These changes in turn impacted the levels of uric acid and uridine metabolite biomarkers, ultimately inhibiting DNA synthesis, suppressing cell proliferation, increasing intracellular ROS levels and reducing ATP content.