Nitrate–Sialin Promotes Dentin Regeneration via Mitochondrial Rewiring

Abstract

The regenerative capacity of dental pulp declines as dental pulp stem cells (DPSCs) enter senescence, compromising pulp–dentin homeostasis, and actionable strategies to restore odontogenesis remain limited. Here, we identify that nitrate acts as a Sialin (SLC17A5)–dependent metabolic cue that promotes dentin regeneration by rewiring mitochondrial metabolism. Across 3 senescence models (natural aging, hydrogen peroxide, and etoposide), nitrate consistently reduced senescence features and restored odontogenic capacity. Silencing Sialin abolished these benefits, establishing pathway necessity. Untargeted metabolomics with pathway enrichment revealed activation of the tricarboxylic acid and pyruvate pathways, accompanied by higher adenosine triphosphate, an increased nicotinamide adenine dinucleotide redox ratio, improved mitochondrial respiratory performance, and lowered mitochondrial reactive oxygen species; these gains were blunted by Sialin loss. Pharmacologic perturbations linked metabolism to phenotype, as electron-transport inhibition negated nitrate’s effects, whereas metabolic modulation partially restored antisenescence and pro-odontogenic outcomes. In a mouse pulp exposure model, local nitrate accelerated dentin bridge formation and tissue repair, but these effects were lost in mesenchymal Sialin conditional-knockout mice. Together, these findings establish a nitrate–Sialin–mitochondria axis that rejuvenates DPSCs, drives dentin regeneration, and restores pulp–dentin homeostasis, while supporting a practical local delivery approach with translational potential for vital pulp therapy.