Hyperglycaemia-induced metabolic stress and epigenetic imprinting in the inflammatory pathogenesis of diabetic neuropathy.

Diabetic neuropathy (DN), a major microvascular complication of diabetes mellitus, results from a complex interplay among oxidative stress, inflammation, and persistent epigenetic modifications. Hyperglycemia-induced mitochondrial dysfunction increases reactive oxygen species (ROS), which activate redox-sensitive inflammatory cascades, including NF-κB, JAK/STAT, and the NLRP3 inflammasome. These pathways amplify cytokine release and neuronal sensitisation, while reciprocal feedback between ROS and inflammation mediated by Nrf2 suppression further perpetuates nerve damage. Damage-associated molecular patterns (DAMPs), including HMGB1, S100A8/A9, mitochondrial DNA, and extracellular ATP, act as key amplifiers of neuroinflammation. By engaging receptors such as RAGE, Toll-like receptors (TLRs), and NOD-like receptors (NLRs), particularly NLRP3, these DAMPs trigger glial activation and nociceptive signalling, contributing to axonal degeneration and pain hypersensitivity in DN. Epigenetic dysregulation, including DNA methylation drift, histone modification imbalance, and aberrant non-coding RNA expression, constitutes a critical mechanism underlying metabolic memory, wherein prior hyperglycemic exposure leaves lasting molecular imprints. Persistent histone acetylation (H3K9ac), altered methylation (H3K4me1/Set7, H3K9me3/SUV39H1), and stable 5-methylcytosine patterns sustain inflammatory and oxidative pathways, even after glucose normalisation. Therapeutically, DNMT and HDAC inhibitors, miRNA modulators, and agents targeting RAGE/TLR4/NLRP3 pathways show promise in reversing these molecular imprints. Antioxidants and anti-inflammatory compounds with epigenetic effects further represent potential disease-modifying strategies. Future research must focus on longitudinal human studies, nerve-specific epigenomics, and multi-omics integration to enable personalised, mechanism-based therapy for DN. Understanding the interdependence of ROS, DAMPs, and epigenetic memory is key to breaking the cycle of chronic neuroinflammation and neuronal injury.