RosA inhibited NF-κB activation and decreased HMGB1 expression in vitro and in vivo. RosA protected the brain against I/R injury by attenuating diabetic brain I/R injury and alleviating the destruction of the BBB, and its protective effect might include the HMGB1 and NF-κB pathways. RosA had therapeutic potential as an anti-inflammatory lead compound useful in primary brain I/R injury in diabetes. Here, HMGB1 is linked to diabetes mellitus.