Cuproptosis Aggravates Pulpitis by Inhibiting the Pentose Phosphate Pathway.

Excessive copper becomes toxic, driving inflammation, and, when copper exceeds a certain threshold, it even leads to a novel programmed cell death termed cuproptosis. However, disordered copper metabolism and its mechanism in pulpitis remain unclear. In this work, we found that lipoteichoic acid (LTA) or lipopolysaccharides (LPS) triggered copper deposition in pulpitis and consequently intensified cuproptosis by impeding the pentose phosphate pathway (PPP). We initially assessed the copper content in pulpitis tissues via inductively coupled plasma mass spectrometry and observed significantly greater concentrations than in healthy pulp tissues. We found that a relatively high copper content was triggered by LTA or LPS, leading cells to cuproptosis. Stimulation of LTA or LPS induced copper deposition and cuproptosis, worsening the progression of pulpitis in vivo. Mechanistically, we found that copper detoxification is dependent on the PPP. We used a 13C-glucose stable isotope-tracing experiment to assess the effect of glucose utilization on cuproptosis. Excessive copper hindered the PPP, resulting in an inadequate generation of nicotinamide adenine dinucleotide phosphate to replenish glutathione and counteract copper toxicity. The PPP regulates the phenotype, function, and survival of preodontoblast-like cells in cuproptosis. Our findings revealed the intricate interplay among bacteria, copper homeostasis, and metabolic reprogramming, providing potential strategies for host-targeted therapy in pulpitis.