Targeting HMGB1 to Attenuate Myocardial Ischaemia-reperfusion Injury (MIRI)-induced Cognitive Dysfunction

Abstract: Myocardial Ischaemia-Reperfusion Injury (MIRI) is increasingly recognized as a contributor to cognitive dysfunction, with High-Mobility Group Box 1 (HMGB1) serving as a pivotal mediator in this heart-brain axis. Released from damaged cardiomyocytes, HMGB1 acts as a Damage-Associated Molecular Pattern (DAMP), activating Toll-Like Receptor 2/4 (TLR2/4) and the Receptor for Advanced Glycation End Products (RAGE), thereby triggering systemic inflamma-tion and neuroinflammation that disrupts Blood-Brain Barrier (BBB) integrity, promotes microglial activation, and induces synaptic dysfunction, ultimately leading to cognitive impairment. This article reviews recent studies on the role of HMGB1 in MIRI and cognitive dysfunction and aims to elucidate its potential interplay with the recently identified adipokine, Meteorin-like (Metrnl), which has also been shown to be critically involved in both MIRI and cognition; subsequently, the HMGB1/Metrnl functional antagonism may be a potential therapeutic mechanism for MIRI-induced cognitive impairment. Addressing the HMGB1/Metrnl interplay offers a pathway to mitigate the long-term disability and loss of independence associated with MIRI-induced cognitive impairment, potentially alleviating the substantial socioeconomic burden and caregiver strain that follows major cardiac events.