SEPHS1, short for Selenophosphate Synthetase 1, is an enzyme-encoding gene. It is crucial in the synthesis of selenophosphate, the active donor of selenium required for selenoprotein biosynthesis [1,2,3,8]. Selenoproteins are involved in antioxidant defense, thyroid hormone metabolism, and cellular homeostasis [1]. The gene has been associated with multiple biological processes and disease-related pathways, making it a subject of significant interest in understanding normal development and disease pathogenesis [1,2,3,4,5,6,7,9]. Genetic models, such as knockout (KO) mouse models, have been instrumental in exploring its functions [4,7,8].

In mouse models, SEPHS1 deficiency leads to various consequences. In embryonic stem cells, SEPHS1 KO has little effect on pluripotency maintenance but impairs differentiation into three germ layers and gastruloid aggregation, especially cardiac differentiation [4]. In adult mice, cartilage-specific Sephs1 knockout causes aging-associated osteoarthritis and augments post-traumatic OA, as SEPHS1 downregulation in chondrocytes elevates reactive oxygen species (ROS) levels and facilitates chondrocyte senescence [3]. SEPHS1 deficiency in mouse embryos affects retinoic signaling and other related signaling pathways, leading to embryonic lethality at E11.5 [2]. In endothelial cells, Sephs1-knockout results in the accumulation of superoxide and lipid peroxide, reduction in nitric oxide, inhibition of cell proliferation and angiogenic tube formation, and cell cycle arrest at G2/M phase [7]. In Drosophila and mice, disruption of the SEPHS1 gene leads to inhibition of cell proliferation, embryonic lethality, and morphological changes [8].

In conclusion, SEPHS1 is essential for various biological processes, including redox homeostasis, cell proliferation, and differentiation. Its deficiency in KO/CKO mouse models has been linked to multiple disease-like conditions such as neurodevelopmental disorders, osteoarthritis, and endothelial cell dysfunction, highlighting its importance in understanding these disease mechanisms.