UFL1 deficiency disrupts skeletal muscle lipid metabolism by promoting the ACC1-FASN axis

Skeletal muscle lipid metabolic homeostasis is essential for normal function and physical performance. Ubiquitin-fold modifier 1 ligase 1 (UFL1), the sole E3 ligase in the UFMylation system, is widely involved in lipid metabolism across various cell types, yet its specific role in skeletal muscle remains unclear. Using skeletal muscle-specific UFL1 knockout mice and UFL1-manipulated C2C12 cells, we found that UFL1 deficiency led to marked lipid droplet accumulation, elevated triglyceride (TG) and total cholesterol (TCH) levels, and upregulation of the lipid droplet coat protein perilipin 2 (PLIN2), whereas UFL1 overexpression reversed these effects. Mechanistically, expression of the lipogenic enzymes acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN) was significantly increased in UFL1-deficient tissues and cells, whereas protein levels of peroxisome proliferator-activated receptor alpha (PPARα) and its downstream target carnitine palmitoyltransferase 1A (CPT1A) remained unchanged, effects reversed by UFL1 overexpression. Collectively, these findings establish UFL1 as a critical regulator of skeletal muscle lipid homeostasis through the ACC1-FASN axis, independent of fatty acid oxidation, revealing a novel target for treating skeletal muscle lipid metabolic dysfunction.