Type 2 diabetes mellitus (T2DM) is increasingly recognised as a driver of cognitive decline, yet the underlying mechanisms remain incompletely understood. We aimed to examine how epigenetic dysregulation, glial necro-inflammatory responses and innate immune signalling collectively contribute to diabetes-related cognitive impairment. Furthermore, we evaluated whether intervention via molecular modulation and exercise ameliorates these pathological changes.

Adult C57BL/6 male mice were fed a high-fat diet for 16 weeks then given a single low-dose streptozotocin injection (100 mg/kg i.p.) to induce diabetes. Cognitive performance was assessed using the Morris Water Maze and Y-maze tests. Hippocampal tissues underwent immunoblotting and qPCR for synaptic markers (PSD-95, synaptophysin), epigenetic regulators (DNMT1/3A, MeCP2), and neurotrophic factors (HSF1, BDNF). A treadmill exercise regimen (30 min/day, 5 days/week for 4 weeks) was applied. Pharmacological interventions included S1PR1 activation (fingolimod) and S1PR2 inhibition (JTE-013). Downstream pathways (pSTAT3–JMJD3, S1PL–p53) were analysed. Markers of necroptosis (RIPK1/RIPK3/MLKL) and activation of the cGAS–STING–IFN-β axis were quantified; inhibitors (Nec-1S for RIPK1, C-176 for STING) were employed to assess therapeutic reversal.

Diabetic mice exhibited pronounced deficits in spatial learning and memory, accompanied by synaptic protein loss, elevated global DNA methylation and reduced HSF1/BDNF expression. Exercise significantly attenuated DNMT expression, restored neurotrophic signalling and improved synaptic integrity. Activation of S1PR1 and inhibition of S1PR2 reduced microglial and astrocyte overactivation via modulation of STAT3–JMJD3 and S1PL–p53 pathways. Necroptosis and STING-mediated immune activation were markedly elevated in diabetic hippocampi; treatment with Nec-1S and C-176 suppressed glial inflammation, rescued mitochondrial function and improved cognition.

Cognitive impairment in T2DM is the result of converging mechanisms including DNA hypermethylation, glial necro-inflammation and activation of necroptotic and STING-driven innate immune pathways. Integrative strategies targeting S1PR signalling, epigenetic enzymes and necroptosis/STING cascades, along with regular exercise, present promising therapeutic avenues for diabetes-associated neurodegeneration.