DDRGK1 (DDRGK domain containing 1) is a critical component of the UFM1 ribosome E3 ligase (UREL) complex that catalyzes ufmylation, a ubiquitin-like post-translational modification 1. The protein's primary function involves regulating endoplasmic reticulum (ER) homeostasis through two key mechanisms: ribosome recycling and ER-phagy. DDRGK1 tethers the UREL complex to the ER membrane and facilitates ufmylation of ribosomal protein RPL26, promoting 60S ribosome dissociation and recycling 1. Additionally, DDRGK1 is essential for ER-phagy by promoting ufmylation of ER proteins like RPN1, which helps degrade damaged ER and suppress the unfolded protein response via IRE1α regulation 1. The protein also stabilizes key transcription factors including p53 by antagonizing ubiquitination and proteasomal degradation 2, and enhances chemoresistance in osteosarcoma through NRF2 stabilization 3. DDRGK1 is crucial for cartilage development by stabilizing SOX9 protein 4. Loss-of-function mutations cause Shohat-type spondyloepimetaphyseal dysplasia, characterized by severe short stature and skeletal abnormalities 5. The protein also plays roles in DNA damage response, autophagy initiation, and acute kidney injury protection 678.