Exosome‐Derived CDC42 From Hypoxia‐Pretreated Neural Stem Cells Inhibits ACSL4‐Related Ferroptosis to Alleviate Vascular Injury in Parkinson's Disease Mice Models

ABSTRACT Parkinson's disease (PD) is a neurodegenerative disorder that gets exacerbated by vascular injury. Neural stem cell‐derived exosomes (NSC‐Exos) display effective neuroprotective properties in PD models. Cell division control protein 42 (CDC42) is connected to angiogenesis, but its effects in PD remain undefined. This research aims to reveal the role of CDC42 in PD. First, we applied 1‐methyl‐4‐phenylpyridinium (MPP + ) to induce the human cerebral microvascular endothelial cells (HCMECs) model and evaluated cell viability and ferroptosis. Then, we characterized NSC‐Exos. Next, to appraise the effect of hypoxia‐pretreated NSC‐Exos (H‐NSC‐Exos) on the MPP + ‐induced cells model, we examined angiogenesis and ferroptosis in HCMECs. Moreover, we constructed the PD mice model using 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and tested the behavioral experiments and vascular injury of mice. Furthermore, we examined cellular ferroptosis and angiogenesis after knockdown of CDC42. Additionally, we investigated the interaction of CDC42 with Acyl‐CoA synthetase long‐chain family member 4 (ACSL4) and detected cellular ferroptosis and angiogenesis after overexpression of ACSL4. We found that H‐NSC‐Exos reversed the MPP + ‐induced decrease in HCMECs viability and migration, lowered lipid‐reactive oxygen species (lipid‐ROS) levels, suppressed ferroptosis, and facilitated angiogenesis. Moreover, H‐NSC‐Exos attenuated MPTP‐induced PD development, vascular injury, and ferroptosis in mice. H‐NSC‐Exos with the knockdown of CDC42 reduced cell viability and angiogenesis and raised ferroptosis and lipid‐ROS levels, which were reversed by ferrostatin‐1 and liproxstatin‐1. CDC42 interacted with ACSL4. Furthermore, overexpression of ACSL4 aggravated the above effects of H‐NSC‐Exos in which CDC42 was knocked down. Our study reveals that H‐NSC‐Exos‐derived CDC42 inhibited ACSL4‐related ferroptosis to alleviate vascular injury in PD mice models. CDC42 may serve as a potent therapeutic target for PD treatment. image