AimsObstructive sleep apnea (OSA) combined with type 2 diabetes (T2DM) may lead to cognitive dysfunction. We previously reported that cognitive impairment is exacerbated in KKAy mice exposed to intermittent hypoxia (IH), during which the DNA binding protein HMGB1 mediates hippocampal neuronal apoptosis by maintaining microglia-associated neuroinflammation, but the underlying mechanism remains largely unknown. Materials and methodsWe performed immunofluorescence, Western blotting, and immunohistochemistry experiments in mouse hippocampal tissues and HT22 cells. KKAy type 2 diabetes model mice and normal C57BL/6J mice were exposed to IH or intermittent normoxia. HT22 cells were cultured in high glucose medium and exposed to IH or intermittent normoxia. We transfected HMGB1 siRNA into HT22 cells and then treated them with high glucose combined with intermittent hypoxia. Key findingsIn conclusion, IH aggravated apoptosis and autophagy defects in T2DM mice, and increased the protein expression of HMGB1 and TLR4. This was also confirmed in HG + IH-treated hippocampal HT22 cells. HMGB1 siRNA can significantly reduce the protein expression of HMGB1 and TLR4, reverse neuronal apoptosis and enhance autophagy. SignificanceWe believe that HMGB1 is a key factor in the regulation of hippocampal neuronal apoptosis and autophagy defects in T2DM combined with OSA. Targeting HMGB1/TLR4 signaling as a novel approach may delay or prevent the increased apoptosis and decreased autophagy induced by T2DM combined with OSA, and may ultimately improve cognitive dysfunction.