Fbxl12, also known as F box and leucine-rich repeat protein 12, is a component of the Skp1-Cul1-F box (SCF) E3 ubiquitin ligase complex. It plays crucial roles in multiple biological processes, such as regulating protein degradation, cell cycle progression, and stem cell differentiation. It is involved in pathways like Fanconi anemia (FA) signaling, ferroptosis regulation, and is associated with cancer, placental development, T-cell differentiation, and sleep regulation [1,2,3,4,5]. Genetic models, especially KO/CKO mouse models, have been valuable in studying its functions.

In KO mouse models, FBXL12 deficiency led to abnormal placental development with impaired junctional zone formation due to ALDH3 accumulation, indicating its essential role in trophoblast differentiation [4]. In T-cell differentiation, FBXL12-null mice showed a differentiation block at the DP-SP transition associated with ALDH3 accumulation in DP cells, suggesting a cell-autonomous function of the FBXL12-ALDH3 axis in thymocyte maturation [5]. In cancer research, depletion of FBXL12 exacerbated oncogene-induced replication stress and sensitized cancer cells to drug-induced replication stress by WEE1 inhibition, making it a potential therapeutic target in CYCLIN E-overexpressing cancers [1].

In conclusion, Fbxl12 is essential for various biological functions including placental development, T-cell differentiation, and cancer cell survival under replication stress. Studies using KO/CKO mouse models have provided insights into its role in these processes, especially in the context of placental and T-cell development as well as in cancer, highlighting its potential as a therapeutic target in certain cancer types.