Calcium/Calmodulin-Dependent Protein Kinase II β Regulates Autophagy Dependent Ferroptosis of Neurons after Cerebral Ischemic Injury by Activating the AREG/JUN/ELAVL1 Pathway

Ferroptosis is an iron-dependent regulatory cell death characterized by lipid peroxidation. The molecular mechanism of calcium/calmodulin-dependent protein kinase II β (CAMK2B) affecting cerebral ischemic injury through autophagy-dependent Ferroptosis is still unclear. Here, we aimed to study the regulatory effect of CAMK2B on autophagy-dependent Ferroptosis and its effect on cerebral ischemic injury. We found that CAMK2B was significantly upregulated in oxygen and glucose deprivation/recovery (OGD/R)-induced PC12 cells and primary hippocampal neurons. CAMK2B knockdown inhibited OGD/R-induced autophagy-dependent Ferroptosis in PC12 cells and primary hippocampal neurons. In addition, CAMK2B was co-localized with Amphiregulin (AREG) in PC12 cells, and overexpression of AREG reversed the effect of CAMK2B knockdown on OGD/R-induced autophagy-dependent Ferroptosis in PC12 cells and primary hippocampal neurons. Further molecular mechanism studies showed that AREG enhanced the transcriptional activation of embryonic lethal abnormal vision-like 1 (ELAVL1) through Jun Proto-Oncogene (c-Jun), thereby inducing autophagy-dependent Ferroptosis in PC12 cells and primary hippocampal neurons. Moreover, CAMK2B was significantly upregulated in the ipsilateral penumbra neurons of cerebral ischemia-reperfusion (I/R) mice, and the level of autophagy-dependent Ferroptosis was increased in the brain tissue of I/R mice. Knockdown of CAMK2B alleviated neuronal damage by inhibiting autophagy-dependent Ferroptosis in the brain tissue of model mice. This study suggests that CAMK2B plays a key role in regulating neuronal autophagy-dependent Ferroptosis, and CAMK2B may be a potential target for the treatment of cerebral I/R injury.

Amphiregulin; Autophagy-dependent ferroptosis; Calcium/calmodulin-dependent protein kinase II Β; Cerebral ischemia-reperfusion injury; Embryonic lethal abnormal vision-like 1; Jun proto-oncogene.