CLIC1 down-regulates Nrf2/HO-1 signalling pathway promoting the apoptosis and pyroptosis in OGD/R-treated HT22 cells

Cerebral ischemia-reperfusion injury (CIRI) occurs during the treatment of ischemic stroke when the affected blood vessels are recanalized and the oxygen supply to the brain is restored. Chloride intracellular channel 1 (CLIC1) and the nuclear factor erythroid-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway have been implicated in many neurological disorders. However, the exact mechanism by which CLIC1 contributes to CIRI remains unclear, and its potential role in modulating the Nrf2/HO-1 signaling pathway in CIRI has yet to be explored. We investigated the potential roles of CLIC1 in CIRI using an oxygen and glucose deprivation/reoxygenation (OGD/R) model in HT22 cells. The findings of our study indicated that CLIC1 was high-expressed after OGD/R and had an inhibitory effect on the Nrf2/HO-1 signalling pathway. This process led to an exacerbation of apoptosis due to oxidative stress and an increase in the activity of the nucleotide-binding oligomeriation domain-like receptor protein 3 (NLRP3) inflammasome and pyroptosis in OGD/R-treated HT22 cells. These effects were reversed when CLIC1 was silenced. Together, the results of this study confirm our hypothesis that CLIC1 promotes CIRI by suppressing the Nrf2/HO-1 signalling pathway. CLIC1 emerges as a promising therapeutic target to prevent neuronal cell injury in CIRI.