USP15 as a Potential Therapeutic Target in Cerebral Ischemia: Modulation of Ferroptosis and Cognitive Dysfunction via the Nrf2/GPX4 Axis in Mice

This study aimed to investigate the role of ubiquitin-specific peptidase 15 (USP15) in ischemic cognitive dysfunction using a mouse model and a cerebral ischemia (CI) cell model, its impact on ferroptosis and the underlying mechanisms. Oxygen-glucose deprivation/reoxygenation (OGD/ R)-induced HT-22 cells were used to establish the CI cell model, and mice induced with CI were used as the animal model for ischemic cognitive dysfunction. Cell damage was evaluated using Cell Counting Kit-8 (CCK-8), flow cytometry (FCM), immunoblotting, and immunofluorescence assays. Cognitive dysfunction in the CI mice was assessed through water maze experiments. Ferroptosis was examined with an iron detection kit and immunoblotting, oxidative stress was evaluated using 2',7'-dichlorofluorescin diacetate (DCF) and enzyme-linked immunosorbent assay (ELISA), and mechanistic experiments were performed via immunoblotting. USP15 knockdown alleviated OGD/ R-induced damage in HT-22 cells. In vivo, USP15 depletion mitigated brain injury in middle cerebral artery occlusion (MCAO) mice and improved learning and memory function. The absence of USP15 reduced oxidative stress in MCAO mice and attenuated ferroptosis by activating nuclear factor erythroid 2-related factor 2 (Nrf2). Mechanistic investigations confirmed that USP15 depletion ameliorated cognitive impairment and ferroptosis through the activation of the Nrf2/ GPX4 axis. USP15 is associated with ferroptosis and cognitive dysfunction in mice and could serve as a potential therapeutic target in CI.