UBE2T-driven lipid metabolic reprogramming links chronic inflammation to pancreatic cancer progression

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy closely associated with chronic inflammation. However, the molecular link between persistent inflammatory signaling and lipid metabolic reprogramming during PDAC progression remains incompletely understood. We investigated the role of ubiquitin-conjugating enzyme E2T (UBE2T) in this process.

The effects of UBE2T were evaluated using cellular functional assays, lipidomic profiling, pathway-rescue experiments, and genetically engineered mouse models under chronic inflammatory conditions. The therapeutic effects of β-1,2,3,4,6-pentagalloylglucose (PGG), previously identified as a pharmacological inhibitor of UBE2T, were further assessed in vitro and in vivo.

Inflammatory stimulation increased UBE2T expression, whereas UBE2T depletion suppressed PDAC cell proliferation and motility- and invasion-associated phenotypes. Lipidomic analyses revealed extensive UBE2T-dependent remodeling of pancreatic lipid profiles and reduced lipid accumulation following UBE2T loss. UBE2T depletion decreased AKT phosphorylation, sterol regulatory element-binding protein (SREBP1) nuclear accumulation, and fatty acid synthase (FASN) expression. AKT activation partially rescued these alterations, whereas SREBP1 knockdown or AKT inhibition attenuated UBE2T-induced TG accumulation, supporting the involvement of the AKT/SREBP1/FASN axis. In vivo, UBE2T deficiency alleviated inflammation-associated pancreatic pathological progression and reduced pancreatic lipid accumulation. PGG treatment similarly reduced lesion burden, FASN expression, and pancreatic lipid accumulation, with concomitant attenuation of stromal remodeling.

UBE2T links chronic inflammatory signaling to AKT/SREBP1/FASN-associated lipid metabolic reprogramming during PDAC progression. UBE2T deficiency and PGG treatment attenuated pancreatic pathological progression and lipid metabolic remodeling, supporting UBE2T as a potential therapeutic target for PDAC.