Pebp1, also known as Raf kinase inhibitor protein (RKIP), is a scaffold protein that inhibits protein kinase cascades. It is involved in multiple key cellular processes, such as cell proliferation, differentiation, and death regulation. Pebp1 is associated with pathways like MAPK, GRK2, and NF-κB, playing a crucial role in maintaining cell integrity [5]. Genetic models, especially KO/CKO mouse models, can be valuable for studying its functions in vivo.

Pebp1 has been found to complex with 15-lipoxygenase isoforms (15LO1 and 15LO2), changing their substrate competence to generate hydroperoxy-PE, which is related to ferroptosis. Inadequate reduction of hydroperoxy-PE due to GPX4 insufficiency or dysfunction leads to ferroptosis. Pebp1-dependent regulatory mechanisms of ferroptotic death are important in airway epithelial cells in asthma, kidney epithelial cells in renal failure, and cortical and hippocampal neurons in brain trauma [1]. Also, in OA, restoring Pebp1 expression by XJB-5-131 protects chondrocytes from ferroptosis [3]. In CUMS-induced depression mouse models, the PEBP1-GPX4-mediated ferroptosis could be involved in the antidepressant mechanism of Xiaoyaosan [2]. Inactivation of RIP3 kinase in mice makes them more sensitive to 15LOX/PEBP1-mediated ferroptotic death, as PEBP1 can complex with RIP3 to inhibit necroptosis, and 15LOX can take PEBP1 from RIP3 to promote ferroptosis [4]. In asthmatic epithelial cells, PEBP1 acts as a regulator between prosurvival autophagy and ferroptotic death [6].

In conclusion, Pebp1 is essential in regulating multiple biological processes, especially in the context of ferroptosis-related diseases such as asthma, renal failure, brain trauma, osteoarthritis, and depression. The use of KO/CKO mouse models has significantly contributed to understanding its role in these disease conditions, providing potential new targets for drug discovery.