CDGSH iron sulfur domain 2 overexpression alleviates neuronal ferroptosis and brain injury by inhibiting lipid peroxidation via AKT/mTOR pathway following intracerebral hemorrhage in mice

Ferroptosis has been implicated in the pathogenesis of secondary brain injury following intracerebral hemorrhage (ICH), and regulating this process is considered a potential therapy for alleviating further brain injury. A previous study showed that CDGSH iron sulfur domain 2 (CISD2) can inhibit Ferroptosis in Cancer. Thus, we investigated the effects of CISD2 on Ferroptosis and the mechanisms underlying its neuroprotective role in mice after ICH. CISD2 expression markedly increased after ICH. CISD2 overexpression significantly decreased the number of Fluoro-Jade C-positive neurons and alleviated brain edema and neurobehavioral deficits at 24 h after ICH. In addition, CISD2 overexpression upregulated the expression of p-AKT, p-mTOR, ferritin heavy chain 1, Glutathione Peroxidase 4, Ferroportin, glutathione, and Glutathione Peroxidase activity, which are markers of Ferroptosis. Additionally, CISD2 overexpression downregulated the levels of malonaldehyde, iron content, acyl-CoA synthetase long-chain family member 4, Transferrin Receptor 1, and cyclooxygenase-2 at 24 h after ICH. It also alleviated mitochondrial shrinkage and decreased the density of the mitochondrial membrane. Furthermore, CISD2 overexpression increased the number of GPX4-positive neurons following ICH induction. Conversely, knockdown of CISD2 aggravated neurobehavioral deficits, brain edema, and neuronal Ferroptosis. Mechanistically, MK2206, an Akt Inhibitor, suppressed p-AKT and p-mTOR, and reversed the effects of CISD2 overexpression on markers of neuronal Ferroptosis and acute neurological outcome. Taken together, CISD2 overexpression alleviated neuronal Ferroptosis and improved neurological performance, which may be mediated through the Akt/mTOR pathway after ICH. Thus, CISD2 may be a potential target to mitigate brain injury via the anti-ferroptosis effect after ICH.

CISD2; Intracerebral hemorrhage; brain injury; ferroptosis; lipid peroxidation.