UFL1 (UFM1 specific ligase 1) is an E3 ubiquitin-like ligase that catalyzes ufmylation, the covalent attachment of UFM1 to target proteins 1. This modification regulates multiple critical cellular processes. In ribosome homeostasis, UFL1 mediates mono-ufmylation of RPL26/uL24, promoting recycling of free 60S ribosomal subunits from the endoplasmic reticulum following translation termination or ribosome stalling. During endoplasmic reticulum stress, UFL1-catalyzed ufmylation of proteins like RPN1 and CYB5R3 promotes reticulophagy and protein degradation 2. UFL1 functions in DNA damage responses by localizing to double-strand break sites and ufmylating histone H4 and MRE11 1. Mechanistically, UFL1 stabilizes p53 by ufmylation, antagonizing MDM2-mediated ubiquitination and promoting p53 accumulation 1. In immune regulation, UFL1 negatively controls T-cell activation by ufmylating PD-1, promoting its stability and limiting CD8+ T-cell responses; UFL1 inhibition enhances anti-tumor immunity 3. Clinically, UFL1 dysregulation associates with multiple cancers. Loss of UFL1 expression correlates with reduced p53 levels in renal cell carcinomas 1, while Akt-phosphorylated UFL1 promotes metastasis through ArpC4 ufmylation-mediated lamellipodia formation 4. UFL1 also regulates replication fork stability in BRCA-deficient cells through PTIP ufmylation 5. Tissue-specific UFL1 deletion causes organ atrophy and endoplasmic reticulum stress, indicating essential homeostatic functions 6.