B355252 Targets UCP2 to Rescue Intracerebral Hemorrhage-Induced Injury by Promoting Mitochondrial Fusion and Inhibiting Ferroptosis

Intracerebral hemorrhage (ICH), a subtype of stroke, is associated with extremely high mortality and disability rates. The small-molecule compound B355252 exhibits neuroprotective effects against oxidative stress and ferroptosis. However, whether B355252 exerts protective effects against ICH-induced injury remains undefined. Furthermore, the therapeutic time window of B355252 for ICH has not been systematically elucidated. Therefore, this study aims to investigate the therapeutic effects of B355252 on ICH, elucidate its role and underlying mechanisms in inhibiting ICH progression, and determine its therapeutic time window. In this study, a mouse model of collagenase-induced intracerebral hemorrhage was established. Multifaceted assessments included histopathological analysis, behavioral tests, transmission electron microscopy (TEM), and lipid peroxidation assays. Results showed that B355252 significantly reduced the hematoma volume and improved neurological deficits in ICH mice. Mechanically, B355252 regulated mitochondrial dynamics and enhanced mitochondrial structural integrity by targeting uncoupling protein 2 (UCP2), leading to upregulation of the fusion protein MFN2 and inhibition of the fission protein FIS1. In addition, B355252 significantly inhibited oxidative stress by maintaining mitochondrial homeostasis, thereby reducing lipid peroxidation and alleviating ferroptosis. Notably, safety assessment confirmed no organ toxicity and extended the treatment time window to 8.5 h. In conclusion, B355252 is a novel UCP2 agonist that maintains mitochondrial function by regulating mitochondrial dynamics and inhibits ferroptosis by mitigating oxidative stress. It overcomes the critical 6-h treatment time window limitation in the ICH model, paving the way for novel research directions in ICH treatment.