DDRGK1, or DDRGK domain-containing protein 1, is an important component of the ufmylation system [5,6,7]. It is involved in multiple biological pathways, such as endoplasmic reticulum (ER)-phagy, mitochondrial oxidative phosphorylation, and regulation of the NF-κB signaling pathway [1,2,6,8]. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, have been crucial in studying its functions, which are essential for normal growth, development, and homeostasis [3,4].

In osteosarcoma, DDRGK1 knockout attenuates NRF2 stability, leading to ROS accumulation, enhanced apoptosis, and increased chemosensitivity to doxorubicin and etoposide [1]. In acute kidney injury, overexpression of DDRGK1 in HK-2 cells enhances ER-phagy, reducing ER stress and apoptosis [2]. In spondyloepiphyseal dysplasia, Ddrgk1 knockout mice show thickened hypertrophic zone in the growth plate, and DDRGK1 stabilizes IRE1α to maintain ER homeostasis [3]. In cartilage development, Ddrgk1-/-mice have limb development defects, and conditional knockout in limb mesenchymal cells leads to limb shortening and joint abnormalities [4]. Also, DDRGK1 deficiency in mouse embryonic fibroblasts affects autophagy by promoting autophagy induction and blocking autophagy degradation [7].

In conclusion, DDRGK1 plays diverse and essential biological functions, revealed through KO/CKO mouse model-based research. It impacts processes related to cancer chemoresistance, kidney injury, skeletal development, and autophagy. These findings offer potential therapeutic targets for diseases such as osteosarcoma, acute kidney injury, and spondyloepiphyseal dysplasia.