GFAT2-mediated HSPD1 O-GlcNAcylation drives chemotherapy resistance in non-small cell lung cancer

作者：Man Zhu, Tang Xl, Zeren Zhu, Wenda Tang, Yumeng Cheng, Wenjuan Tang, Qianqian Zhang, Longyu Qin, Yongfang Yao, Youqi Zhang · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2026 · DOI：10.1186/s13046-026-03674-x · 被引用次数：1 · 研究领域：Glycosylation and Glycoproteins Research、Galectins and Cancer Biology、Proteoglycans and glycosaminoglycans research

BACKGROUND: Non-small cell lung cancer (NSCLC) patients often develop resistance to first-line etoposide/cisplatin (EP) chemotherapy. However, available studies only focus on single-agent resistance to either etoposide or cisplatin in NSCLC. Hence, a notable knowledge gap exists in terms of the mechanisms underlying multidrug resistance, particularly within a system that recapitulates EP resistance in NSCLC. This emphasizes an urgent need for new strategies to tackle this challenge. METHODS: This study established a chemotherapy-resistant xenograft mouse model that mimicked the clinical chemotherapy regimens used for patients with NSCLC and aimed to explore the molecular mechanisms that contribute to chemotherapy resistance in NSCLC. The key protein that regulates chemotherapy resistance in NSCLC were identified through proteomics and co-immunoprecipitation mass spectrometry (Co-IP/MS) analyses, and revealed its regulatory mechanisms. RESULTS: This study identified glutamine-fructose-6-phosphate transaminase 2 (GFAT2,) as a key driver of resistance, upregulated in chemoresistant NSCLC cells. GFAT2 critically regulates the hexosamine biosynthetic pathway (HBP), enhancing uridine diphosphate-GlcNAc (UDP-GlcNAc) synthesis and overall O-GlcNAcylation. Specifically, GFAT2 augments O-GlcNAcylation of heat shock protein family D member 1 (HSPD1) at residue T320. This modification stabilizes HSPD1 by blocking its tripartite motif containing 21 (TRIM21)-mediated ubiquitination and deg...