HMGB1 plays an important role in pyroptosis induced blood brain barrier breakdown in diabetes-associated cognitive decline.

Diabetes mellitus increases the risk of dementia, and evidence suggests hyperglycemia is a key contributor to neurodegeneration. However, our understanding of diabetes-associated cognitive decline, an important complication of diabetes mellitus, is lacking and the underlying mechanism is unclear. Blood brain barrier (BBB) breakdown is a possible cause of dementia in diabetes mellitus and Alzheimer's disease. Accumulating evidence shows BBB dysfunction caused by hyperglycemia contributes to cognitive decline. A specific type of inflammatory programmed cell death, called pyroptosis, has potential as a therapeutic target for BBB-associated diseases. Potential inducers of pyroptosis include inflammasomes such as NLRP3, whose activation relies on damage-associated molecular patterns. High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein found in most cell types, and acts as a damage-associated molecular pattern when released from the nucleus. We propose that HMGB1 influences vascular inflammation by activating the NLRP3 inflammasome and thereby initiating pyroptosis in vascular cells. Moreover, HMGB1 plays a pivotal role in the pathogenesis of diabetes mellitus and diabetic complications. Here, we review the role of HMGB1 in BBB dysfunction induced by hyperglycemia and propose that HMGB1 is a promising therapeutic target for countering diabetes-associated cognitive decline.