Keap1, short for Kelch-like ECH-associated protein 1, is a crucial protein in the Nrf2-Keap1 signaling pathway. This pathway serves as a key intracellular defense mechanism against oxidative and electrophilic stresses of exogenous and endogenous origins [1,2,3,4,5,7,8,9]. Keap1 acts as a cysteine thiol-rich sensor of redox insults, and under normal conditions, it binds to Nrf2, a transcription factor, targeting it for proteasomal degradation [3]. This signaling pathway is evolutionarily conserved and plays a significant role in maintaining redox homeostasis, cell proliferation, differentiation, and cytoprotection [1,3]. Genetic models, such as KO/CKO mouse models, have been valuable in studying Keap1's functions.

In various disease pathologies, the Keap1-Nrf2 pathway has been extensively studied. In breast cancer, KEAP1 acts as a tumor suppressor, promoting HSPA9 degradation and controlling mitochondrial biogenesis [6]. In preeclampsia, the NRF2/KEAP1 signaling pathway is involved in protecting cells against oxidative damage due to increased reactive oxygen species (ROS) levels [8]. In angiogenesis and vascular diseases, appropriate regulation of oxidative stress mediated via the Keap1-Nrf2 pathway can be beneficial in diseases associated with abnormal angiogenesis, like diabetes and cancers. Also, Nrf2 deficiency, which can be related to Keap1's function, leads to impaired survival, proliferation, and angiogenic capacity of endothelial cells in a hind limb ischemia model [9].

In conclusion, Keap1 is essential in the Nrf2-Keap1 signaling pathway, which is crucial for maintaining redox homeostasis and has implications in multiple biological processes. Model-based research, especially KO/CKO mouse models, has revealed Keap1's role in various disease areas such as breast cancer, preeclampsia, and angiogenesis-related diseases, providing insights into potential therapeutic targets [6,8,9].

References:

1. Bellezza, Ilaria, Giambanco, Ileana, Minelli, Alba, Donato, Rosario. 2018. Nrf2-Keap1 signaling in oxidative and reductive stress. In Biochimica et biophysica acta. Molecular cell research, 1865, 721-733. doi:10.1016/j.bbamcr.2018.02.010. https://pubmed.ncbi.nlm.nih.gov/29499228/

2. Ulasov, Alexey V, Rosenkranz, Andrey A, Georgiev, Georgii P, Sobolev, Alexander S. 2021. Nrf2/Keap1/ARE signaling: Towards specific regulation. In Life sciences, 291, 120111. doi:10.1016/j.lfs.2021.120111. https://pubmed.ncbi.nlm.nih.gov/34732330/

3. Yamamoto, Masayuki, Kensler, Thomas W, Motohashi, Hozumi. . The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. In Physiological reviews, 98, 1169-1203. doi:10.1152/physrev.00023.2017. https://pubmed.ncbi.nlm.nih.gov/29717933/

4. Adinolfi, Simone, Patinen, Tommi, Jawahar Deen, Ashik, Küblbeck, Jenni, Levonen, Anna-Liisa. 2023. The KEAP1-NRF2 pathway: Targets for therapy and role in cancer. In Redox biology, 63, 102726. doi:10.1016/j.redox.2023.102726. https://pubmed.ncbi.nlm.nih.gov/37146513/

5. Yu, Chao, Xiao, Jian-Hui. 2021. The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging. In Oxidative medicine and cellular longevity, 2021, 6635460. doi:10.1155/2021/6635460. https://pubmed.ncbi.nlm.nih.gov/34012501/

6. Han, Bing, Zhen, Fang, Sun, Yue, Li, Shui-Jie, Hu, Jing. 2024. Tumor suppressor KEAP1 promotes HSPA9 degradation, controlling mitochondrial biogenesis in breast cancer. In Cell reports, 43, 114507. doi:10.1016/j.celrep.2024.114507. https://pubmed.ncbi.nlm.nih.gov/39003742/

7. Jaramillo, Melba C, Zhang, Donna D. . The emerging role of the Nrf2-Keap1 signaling pathway in cancer. In Genes & development, 27, 2179-91. doi:10.1101/gad.225680.113. https://pubmed.ncbi.nlm.nih.gov/24142871/

8. Tossetta, Giovanni, Fantone, Sonia, Piani, Federica, Giannubilo, Stefano Raffaele, Marzioni, Daniela. 2023. Modulation of NRF2/KEAP1 Signaling in Preeclampsia. In Cells, 12, . doi:10.3390/cells12111545. https://pubmed.ncbi.nlm.nih.gov/37296665/

9. Guo, Zi, Mo, Zhaohui. 2020. Keap1-Nrf2 signaling pathway in angiogenesis and vascular diseases. In Journal of tissue engineering and regenerative medicine, 14, 869-883. doi:10.1002/term.3053. https://pubmed.ncbi.nlm.nih.gov/32336035/