UFMylation: biology mechanisms, functions, and clinical implications

Over the past two decades, UFMylation, a crucial post-translational modification mediated by a canonical E1–E2–E3 enzymatic cascade and specific deUFMylation enzymes, has emerged as an essential component for maintaining cellular homeostasis. It plays indispensable regulatory roles in fundamental processes, including protein quality control, genomic stability maintenance, cell fate determination, and modulation of immune responses. These functions are achieved by precisely regulating key protein substrates and their associated signaling pathways. Consequently, dysregulation of these UFMylation-regulated processes directly drives the pathogenesis of a broad spectrum of human diseases. This review summarizes current insights into the UFMylation machinery, its enzymatic cascade, and related fundamental cellular processes. We systematically explain the molecular mechanisms by which UFMylation regulates cellular functions and discuss how its dysfunction contributes to the pathogenesis of a wide range of human diseases, including cancers, skeletal dysplasias, hematological disorders, nervous system disorders, metabolic-associated liver disease, silicosis, and cardiovascular diseases. Deciphering the precise molecular mechanisms underlying these pathologies is crucial for identifying diagnostic biomarkers and developing targeted therapeutic strategies. Furthermore, we highlight future perspectives on targeting the UFMylation system for therapeutic intervention in these diseases.