Zinc induces neuronal autophagy via HMGB1 nuclear translocation in acute cerebral ischemia

The process of autophagy following a stroke is a highly complex phenomenon. Damaged brain cells can produce multifactorial signals that may act as activators of autophagy. Zinc, which is abundantly present in the central nervous system, regulates numerous biological processes, including autophagy. Studies conducted on mammalian cells have consistently demonstrated that zinc promotes autophagy. However, the precise mediator of zinc-induced autophagy following acute ischemic stroke remains unclear. In this study, we investigated whether High Mobility Group Box 1 (HMGB1) is involved in the process of zinc-mediated neuronal autophagy after cerebral ischemia. We established a rat model of middle cerebral artery occlusion (MCAO), and our results indicated that chelating zinc significantly reduced infarct volume and improved neurological function after acute ischemic stroke. Additionally, chelating zinc diminished ischemia-induced neuronal autophagy and inhibited the translocation of HMGB1 from the nucleus to the cytoplasm during acute cerebral ischemia. In cellular experiments utilizing oxygen-glucose deprivation (OGD) treatment, we found that excessive intracellular zinc facilitates the translocation of HMGB1 from the nucleus to the cytoplasm, while HMGB1 regulates zinc-mediated autophagy. Furthermore, inhibiting HMGB1 in cultured neurons impeded the effects of zinc on autophagy. These findings provide evidence that zinc mediates neuronal autophagy by regulating the translocation of HMGB1 to the cytoplasm during acute ischemic stroke.