Remimazolam Inhibits Neuronal Apoptosis, Inflammation, and Ferroptosis in Cerebral Infarction via Promoting TRIM67‐Mediated Degradation of ACSL4

Cerebral infarction is one of the most common ischemic cerebrovascular diseases that can lead to neurological deficits. Remimazolam (RE) is a sedative agent that has been shown to improve neurological disorders. However, the underlying molecular mechanism of RE for the treatment of cerebral infarction remains to be further explored. Oxygen-glucose deprivation/reperfusion (OGD/R) cell model and middle cerebral artery occlusion (MCAO) rat model were constructed. Cell proliferation, apoptosis, and inflammation were evaluated using CCK8 assay, EdU assay, flow cytometry, and ELISA. Ferroptosis-related markers were assessed by commercial kits. The expression of Acyl-CoA synthetase long-chain family member 4 (ACSL4) and tripartite motif-containing 67 (TRIM67) was examined by qRT-PCR or western blot. The interaction between TRIM67 and ACSL4 was confirmed by Co-IP assay. Cerebral injury in MCAO rat model was assessed by histological staining and neurological score. RE treatment enhanced proliferation, repressed apoptosis, inflammation and ferroptosis in OGD/R-induced SK-N-SH cells. RE decreased ACSL4 protein expression, and ACSL4 overexpression could reverse the anti-apoptosis, anti-inflammation and anti-ferroptosis roles of RE in OGD/R-induced SK-N-SH cells. TRIM67 reduced ACSL4 expression by increasing its ubiquitination and degradation. TRIM67 alleviated OGD/R-induced neuronal injury by downregulating ACSL4. RE enhanced TRIM67 protein expression, and TRIM67 knockdown also reversed the neuroprotective effect of RE. Also, RE relieved cerebral injury in the MCAO rat model via promoting TRIM67 expression to repress ACSL4. RE alleviated OGD/R-induced apoptosis, inflammation and ferroptosis through promoting TRIM67-mediated degradation of ACSL4, which provided a possible path for additional research in the therapies of cerebral infarction.