Epigenetic regulation in a high-sugar environment (Review)

The prevalence of diabetes and its complications has become a major global health challenge, with its pathological process closely linked to the phenomenon of 'metabolic memory' induced by persistent hyperglycemia. Epigenetic regulation is recognized as the core molecular mechanism underpinning this process. The present review systematically elucidated how the hyperglycemic microenvironment profoundly regulates cellular functions and drives the onset and progression of diabetes and its vascular complications by reprogramming three major epigenetic pathways: DNA methylation, histone modifications and non‑coding RNA expression. The present review elaborated in detail how high glucose induces alterations in the DNA methylation status of specific genes (such as PDX1 and CXCR4) within key target cells including pancreatic β‑cells, hepatocytes, muscle cells and adipocytes; how it modulates multiple histone modifications, including emerging histone lactylation (such as H3K18la), thereby directly activating pathogenic gene transcription; and how it disrupts non‑coding) RNA networks (such as long non‑coding RNA MALAT1 and microRNA 21) to mediate inflammation, oxidative stress and fibrosis by interfering with signaling pathways such as PI3K/Akt and TGF‑β. Furthermore, the present review specifically emphasized the cellular and tissue specificity of high‑glucose‑induced epigenetic regulation, thereby elucidating its unique mode of action in specific complications such as diabetic nephropathy and cardiovascular disease. Finally, the present review considered the substantial potential of targeting key epigenetic enzymes (such as DNA methyltransferases, histone deacetylases) or using epigenetic markers as biomarkers and novel therapeutic strategies. This provides a conceptual framework and directions for ultimately 'eradicating' metabolic memory and achieving precise prevention and treatment of diabetes and its complications.