Combinational Analysis of Metabolomic and O-GlcNAcylation Omics Reveals the HBP Metabolic Regulation of Chemoresistance via GFPT1/NR3C1 O-GlcNAcylation/GPX4 Axis.

ABSTRACT: Dysregulation of ferroptosis is linked to chemoresistance, and reprogramming of glucose metabolism is involved in this progress. However, the underlying mechanisms remain obscure. Herein, using metabolic profiling, we find that hexosamine biosynthetic pathway (HBP) metabolism and the byproduct, UDP-GlcNAc, are substantially up-regulated in chemoresistant tumor tissues and cells. UDP-GlcNAc-derived O-GlcNAcylation levels increase with the decreased ferroptosis and chemosensitivity in cancer cells. Knockout of the rate-limiting enzyme GFPT1 in HBP metabolism inhibits O-GlcNAcylation, induces ferroptosis, and mitigates chemoresistance of orthotopic bladder cancer in Gfpt1^-/- mice. The global O-GlcNAcylation omics mapped the O-GlcNAcylated sites and proteins in resistant and

SUBMITTER: Zhou X 

PROVIDER: S-EPMC12308066 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature