Salivary Citrate Deficiency Defines an Endogenous Dentin Remineralization Failure State Through Glandular MT1/2‐Zn 2+ ‐ACO2 Dysregulation

ABSTRACT Rapid caries progression occurs even when salivary flow and calcium phosphate availability are preserved, suggesting a knowledge gap in how available minerals are used for repair. Early‐stage Sjögren's syndrome was examined as a clinical model of this condition. Salivary citrate was markedly lower in the disease cohort and was inversely associated with caries burden, whereas salivary flow and the major mineral ions did not differ from healthy controls. In mineralization systems with matched calcium and phosphate concentrations, the disease‐associated citrate concentration reduced intrafibrillar mineral deposition, disrupted hydroxyapatite organization, and limited structural and mechanical recovery of demineralized dentin. Human salivary gland tissue, an immunization‐induced rat model, and primary salivary gland epithelial cells showed a similar metabolic pattern: increased metallothionein 1/2 (MT1/2), reduced labile Zn 2+ , increased aconitase 2 (ACO2) activity, and citrate depletion. ZnSO 4 repletion increased intracellular Zn 2+ , reduced ACO2 activity, restored citrate toward control levels, and improved the mineralization activity of epithelial‐cell supernatants. The data indicate that citrate availability influences dentin mineral utilization and associate citrate depletion with glandular MT1/2‐Zn 2+ ‐ACO2 dysregulation. These findings support an association between glandular zinc‐citrate dysregulation and impaired remineralization, suggesting that this mechanism may account for impaired endogenous remineralization despite preserved availability of the major mineral ions.