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重新定义神经退行性疾病治疗：KEAP1、PROTACs与炎症调节剂的协同作用

Redefining Neurodegenerative Treatment: Synergy of KEAP1, PROTACs, and Inflammatory Modulators.

作者信息

Kargbo Robert B

机构信息

Usona Institute, Fitchburg, Wisconsin 53711-5300, United States.

出版信息

ACS Med Chem Lett. 2024 Jan 29;15(2):167-168. doi: 10.1021/acsmedchemlett.4c00001. eCollection 2024 Feb 8.

DOI:10.1021/acsmedchemlett.4c00001
PMID:38352846
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10860189/
Abstract

The KEAP1-NRF2 axis is pivotal in the cellular mechanism against oxidative and electrophilic stress. NRF2, under standard conditions, undergoes proteasomal degradation mediated by the E3 ubiquitin ligase KEAP1. Stress conditions lead to KEAP1 inactivation, facilitating NRF2 stability and subsequent activation of defensive genes. NRF2 signaling anomalies are associated with cancer progression and neurodegenerative diseases. Continuous activation of the NRF2 pathway aids in the survival of cancer cells, while a deficiency in NRF2 functionality intensifies inflammation and oxidative injury in neurodegenerative disease models. Thus, the modulation of this pathway is being investigated for therapeutic applications in both cancer and neurodegenerative diseases.

摘要

KEAP1-NRF2轴在细胞对抗氧化和亲电应激的机制中起关键作用。在标准条件下，NRF2会经历由E3泛素连接酶KEAP1介导的蛋白酶体降解。应激条件会导致KEAP1失活，从而促进NRF2的稳定性以及随后防御基因的激活。NRF2信号异常与癌症进展和神经退行性疾病有关。NRF2通路的持续激活有助于癌细胞存活，而NRF2功能缺陷会加剧神经退行性疾病模型中的炎症和氧化损伤。因此，目前正在研究调节该通路在癌症和神经退行性疾病治疗中的应用。

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本文引用的文献

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Redox regulation of the NLRP3-mediated inflammation and pyroptosis.NLRP3 介导的炎症和细胞焦亡的氧化还原调控。
Biomed Khim. 2023 Dec;69(6):333-352. doi: 10.18097/PBMC20236906333.
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Super-enhancers and the super-enhancer reader BRD4: tumorigenic factors and therapeutic targets.超级增强子与超级增强子读取蛋白BRD4：致癌因子与治疗靶点
Cell Death Discov. 2023 Dec 22;9(1):470. doi: 10.1038/s41420-023-01775-6.
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Recent progress and applications of small molecule inhibitors of Keap1-Nrf2 axis for neurodegenerative diseases.小分子抑制剂 Keap1-Nrf2 轴在神经退行性疾病中的最新进展和应用。
Eur J Med Chem. 2024 Jan 15;264:115998. doi: 10.1016/j.ejmech.2023.115998. Epub 2023 Nov 29.
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Metabolite itaconate in host immunoregulation and defense.代谢物衣康酸在宿主免疫调节和防御中的作用。
Cell Mol Biol Lett. 2023 Dec 2;28(1):100. doi: 10.1186/s11658-023-00503-3.
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Metal profiling in coronary ischemia-reperfusion injury: Implications for KEAP1/NRF2 regulated redox signaling.金属在冠状动脉缺血再灌注损伤中的作用：KEAP1/NRF2 调控的氧化还原信号通路的影响。
Free Radic Biol Med. 2024 Jan;210:158-171. doi: 10.1016/j.freeradbiomed.2023.11.013. Epub 2023 Nov 19.
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Reductive stress in cancer: coming out of the shadows.癌症中的还原应激：走出阴影。
Trends Cancer. 2024 Feb;10(2):103-112. doi: 10.1016/j.trecan.2023.10.002. Epub 2023 Nov 2.