DHFR-Driven Metabolic Memory Sustains Periodontal Tissue Destruction

Abstract

Diabetes mellitus is one of the most common metabolic diseases worldwide, with periodontal tissue destruction being a major complication. Hyperglycemia-induced changes in metabolism and immune responses may lead to persistent periodontal tissue destruction. This study aimed to investigate hyperglycemia-induced chronic periodontal tissue destruction by focusing on dihydrofolate reductase (DHFR) and its role in metabolic memory. We used CD45.2⁺ BKS-Lepr^em2Cd479/Gpt mice and CD45.1⁺ FVB/NJGpt mice to construct metabolic memory and bone marrow transplantation models, respectively. Our findings showed that hyperglycemia induced a persistent inflammatory senescent phenotype in macrophages. Insulin glycemic control was unable to reverse these pathological changes in bone marrow–derived macrophages and gingival tissues. Furthermore, combined metabolomic and transcriptomic analyses revealed reduced DHFR-mediated 1-carbon metabolism under hyperglycemia, with decreased levels of the reduced form of nicotinamide-adenine dinucleotide phosphate and adenosine triphosphate caused by altered glucose metabolism, impairing the function of DHFR. Alterations in DNA methylation may be responsible for memory-like metabolic patterns in macrophages. Finally, DHFR overexpression reversed hyperglycemia-induced persistent metabolic and pathological changes in macrophages. In summary, this study highlights DHFR-mediated metabolic memory in macrophages as a key factor driving hyperglycemia-induced chronic periodontal tissue destruction.