UFM1 (ubiquitin fold modifier 1) is a ubiquitin-like protein that undergoes covalent attachment to lysine residues on substrate proteins through a dedicated enzymatic cascade 1. The ufmylation process requires three key enzymes: the E1 activating enzyme UBA5, the E2 conjugating enzyme UFC1, and the E3 ligase UFL1 1. UFM1 regulates multiple cellular processes, primarily at the endoplasmic reticulum (ER), where it functions in ribosome-associated quality control and reticulophagy (ER-phagy) induced by ER stress 21. UFMylation also stabilizes the tumor suppressor p53 by antagonizing its ubiquitination and proteasome-mediated degradation, with the UFL1 ligase competing with MDM2 for p53 binding 3. Additionally, UFMylation regulates VCP/p97 to stabilize BECN1, facilitating autophagy initiation 4, and modulates SLC7A11 stability to regulate ferroptosis in cancer cells 5. Dysregulation of the UFM1 system has significant clinical implications: mutations in UFMylation pathway genes cause hereditary developmental epileptic encephalopathy and Schotat-type osteochondrodysplasia 6, while reduced UFL1 and DDRGK1 expression correlates with decreased p53 levels in renal cell carcinomas, suggesting therapeutic potential 3.