Pebp1, also known as Raf kinase inhibitor protein (RKIP), is a 21 kDa scaffold protein that plays diverse roles in cells. It is involved in multiple key processes such as regulating protein kinase cascades, with its dysregulation linked to major diseases like cancer and Alzheimer's disease [5,6]. It interacts with various proteins in pathways like MAPK, GRK2, and NF-κB, influencing cell proliferation and differentiation [6].

In terms of ferroptosis, Pebp1 complexes with 15-Lipoxygenase (15LOX) isoforms (15LO1 and 15LO2), changing their substrate specificity to generate hydroperoxy-PE, a crucial step in ferroptosis. Inadequate reduction of hydroperoxy-PE due to GPX4 insufficiency or dysfunction leads to ferroptotic cell death. This mechanism is important in diseases such as asthma, renal failure, and brain trauma [1]. Additionally, inactivation of RIP3 kinase, which normally complexes with Pebp1 to inhibit necroptosis, makes cells more sensitive to 15LOX/Pebp1-mediated ferroptosis [4]. Pebp1-GPX4-mediated ferroptosis may also be involved in the antidepressant mechanism of the traditional Chinese formula Xiaoyaosan, as activation of ferroptosis was found in the hippocampi of CUMS-induced mice [2]. Moreover, in an osteoarthritis mouse model, XJB-5-131 protected chondrocytes from ferroptosis by restoring Pebp1 expression [3].

In summary, Pebp1 is a multifunctional protein with a significant role in regulating cell death processes, especially ferroptosis, which has implications for multiple disease areas including neurodegenerative diseases, mental disorders, and musculoskeletal diseases. Studies using various models, including mouse models, have been crucial in uncovering these functions, highlighting Pebp1 as a potential therapeutic target.

References:

1. Wenzel, Sally E, Tyurina, Yulia Y, Zhao, Jinming, Bayır, Hülya, Kagan, Valerian E. . PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. In Cell, 171, 628-641.e26. doi:10.1016/j.cell.2017.09.044. https://pubmed.ncbi.nlm.nih.gov/29053969/

2. Jiao, Haiyan, Yang, Hongjun, Yan, Zhiyi, Li, Xiaojuan, Chen, Jiaxu. 2021. Traditional Chinese Formula Xiaoyaosan Alleviates Depressive-Like Behavior in CUMS Mice by Regulating PEBP1-GPX4-Mediated Ferroptosis in the Hippocampus. In Neuropsychiatric disease and treatment, 17, 1001-1019. doi:10.2147/NDT.S302443. https://pubmed.ncbi.nlm.nih.gov/33854318/

3. Sun, Wei, Lv, Zhongyang, Li, Weitong, Jiang, Xuefeng, Shi, Dongquan. 2024. XJB-5-131 protects chondrocytes from ferroptosis to alleviate osteoarthritis progression via restoring Pebp1 expression. In Journal of orthopaedic translation, 44, 114-124. doi:10.1016/j.jot.2023.12.005. https://pubmed.ncbi.nlm.nih.gov/38304614/

4. Lamade, Andrew M, Wu, Limin, Dar, Haider H, Whalen, Michael J, Bayır, Hülya. 2022. Inactivation of RIP3 kinase sensitizes to 15LOX/PEBP1-mediated ferroptotic death. In Redox biology, 50, 102232. doi:10.1016/j.redox.2022.102232. https://pubmed.ncbi.nlm.nih.gov/35101798/

5. Schoentgen, Françoise, Jonic, Slavica. 2020. PEBP1/RKIP behavior: a mirror of actin-membrane organization. In Cellular and molecular life sciences : CMLS, 77, 859-874. doi:10.1007/s00018-020-03455-5. https://pubmed.ncbi.nlm.nih.gov/31960115/

6. Rajkumar, Karthik, Nichita, Aare, Anoor, Pawan Kumar, Singh, Surya Satyanarayana, Burgula, Sandeepta. 2016. Understanding perspectives of signalling mechanisms regulating PEBP1 function. In Cell biochemistry and function, 34, 394-403. doi:10.1002/cbf.3198. https://pubmed.ncbi.nlm.nih.gov/27385268/