UFMylation in lipid metabolism disorders-associated diseases

Lipid metabolism is a finely regulated process essential for cellular homeostasis, and its dysregulation contributes to various diseases, such as atherosclerosis and obesity. UFMylation, a ubiquitin-like posttranslational modification involving UFM1 conjugation to target proteins, has emerged as a critical regulator of lipid metabolism. This review systematically outlines the UFMylation cascade, including its enzymatic components (UFSPs, UBA5, UFC1, and UFL1), and its physiological roles in lipid metabolism, endoplasmic reticulum homeostasis, DNA repair, and tissue development. We further highlight the pathogenic implications of UFMylation dysregulation in lipid-related disorders, including atherosclerosis (AS), nonalcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus(T2DM), and cancer, by modulating lipogenesis, lipolysis, and cholesterol efflux. Furthermore, this review underscores UFMylation as a pivotal mechanism in lipid metabolism disorders and proposes directions for mechanistic and translational studies.