Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India.
Mol Biol Rep. 2024 Nov 28;52(1):22. doi: 10.1007/s11033-024-10123-5.
The ubiquitin-proteasome system (UPS) plays a pivotal role in regulating protein homeostasis and cellular processes, including protein degradation, trafficking, DNA repair, and cell signaling. During cerebral ischemia, ischemic conditions profoundly disrupt UPS activity, leading to proteasomal dysfunction and the accumulation of abnormal proteins. This imbalance contributes to neuronal injury and cell death observed in ischemic stroke. The UPS is intricately linked to various signaling pathways crucial for neuronal survival, inflammation, and cellular stress response, such as NF-κB, TRIM, TRIP, JAK-STAT, PI3K/Akt, and ERK1/2. Alterations in the ubiquitination process can significantly impact the activation and regulation of these pathways, exacerbating ischemic brain injury. Therapeutic approaches targeting the UPS in cerebral ischemia aim to rebalance protein levels, reduce proteotoxic stress, and mitigate neuronal injury. Strategies include proteasome inhibition, targeting specific ubiquitin ligases and deubiquitinating enzymes, and modulating ubiquitination-mediated regulation of key signaling pathways implicated in ischemia-induced pathophysiology. Therefore, the present review discusses the molecular mechanisms underlying UPS dysfunction in ischemic stroke is crucial for developing effective therapeutic interventions. Modulating ubiquitination-mediated pathways through therapeutic interventions targeting specific UPS components holds significant promise for mitigating ischemic brain injury and promoting neuroprotection and functional recovery in patients with cerebral ischemia.
泛素-蛋白酶体系统 (UPS) 在调节蛋白质稳态和细胞过程中起着关键作用，包括蛋白质降解、运输、DNA 修复和细胞信号转导。在脑缺血期间，缺血条件会严重破坏 UPS 的活性，导致蛋白酶体功能障碍和异常蛋白质的积累。这种失衡导致缺血性中风中观察到的神经元损伤和细胞死亡。UPS 与各种信号通路密切相关，这些信号通路对神经元存活、炎症和细胞应激反应至关重要，如 NF-κB、TRIM、TRIP、JAK-STAT、PI3K/Akt 和 ERK1/2。泛素化过程的改变会显著影响这些通路的激活和调节，从而加重缺血性脑损伤。针对脑缺血 UPS 的治疗方法旨在重新平衡蛋白质水平、减轻蛋白毒性应激和减轻神经元损伤。策略包括蛋白酶体抑制、靶向特定的泛素连接酶和去泛素化酶，以及调节泛素化介导的与缺血引起的病理生理学相关的关键信号通路的调节。因此，本综述讨论了 UPS 功能障碍在缺血性中风中的分子机制，这对于开发有效的治疗干预措施至关重要。通过针对特定 UPS 成分的治疗干预来调节泛素化介导的途径，为减轻缺血性脑损伤和促进脑缺血患者的神经保护和功能恢复提供了巨大的希望。
