Ufmylation‐Deficient DDRGK1 Ameliorates Obesity by Inhibiting FASN‐Mediated Adipocyte Lipogenesis

ABSTRACT Fatty acid synthase (FASN) is a central regulator of obesity through de novo lipogenesis (DNL), undergoes precise control via the ubiquitin‐proteasome system, yet its obesity‐related post‐translational modifications remain unclear. Our clinical investigation of human adipose tissue (n = 23) demonstrated elevated FASN protein in overweight individuals, mirroring high‐fat diet (HFD) mouse models. However, transcriptomic analysis of 770 GEO samples paradoxically revealed inverse correlation between FASN mRNA and BMI. Mechanistically, we identified DDRGK1 as a UFMylation effector that stabilizes FASN by competitively inhibiting ubiquitination. Genetic disruption of this pathway in Ddrgk1 K268R mutant mice conferred metabolic protection, with 12% reduced body weight and 18% decreased fat mass under HFD conditions, alongside improved glucose homeostasis. Single‐nucleus RNA sequencing of inguinal white adipose tissue (iWAT) demonstrated reprogrammed metabolic flux in mutant mice, complemented by lipidomic profiling showing attenuated DNL. In vitro studies confirmed that DDRGK1 deficiency impairs adipocyte lipid droplet formation (reversible by palmitate acid supplementation) through FASN destabilization. Our work elucidates the adipocyte‐specific DDRGK1‐UFMylation‐FASN axis as a novel therapeutic target for obesity‐associated metabolic dysfunction.