Cover Image

GCLM lactylation mediated by ACAT2 promotes ferroptosis resistance in KRASG12D-mutant cancer

KRAS mutations drive tumorigenesis, but their role in ferroptosis regulation remains unclear. Here, we construct wild-type KRAS (KRASWT) and KRASG12D-mutant cancer cells and demonstrate that G12D-mutant cells exhibit increased viability and reduced ferroptosis upon RSL3 or erastin treatment. These c...

Full description

Saved in:
Bibliographic Details
Main Authors: Chen, Yubin (Author) , Yan, Qian (Author) , Ruan, Shiye (Author) , Cui, Jinwei (Author) , Li, Zhenchong (Author) , Zhang, Zhongyan (Author) , Yang, Jiayu (Author) , Fang, Jike (Author) , Liu, SiYang (Author) , Huang, Shanzhou (Author) , Hou, Baohua (Author) , Zhang, Chuanzhao (Author)
Format: Article (Journal)
Language:English
Published: June 24, 2025
In: Cell reports
Year: 2025, Volume: 44, Issue: 6, Pages: 1-27
ISSN:2211-1247
DOI:10.1016/j.celrep.2025.115774
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.celrep.2025.115774
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2211124725005455
Get full text
Author Notes:Yubin Chen, Qian Yan, Shiye Ruan, Jinwei Cui, Zhenchong Li, Zhongyan Zhang, Jiayu Yang, Jike Fang, SiYang Liu, Shanzhou Huang, Baohua Hou, and Chuanzhao Zhang
Description
Summary:KRAS mutations drive tumorigenesis, but their role in ferroptosis regulation remains unclear. Here, we construct wild-type KRAS (KRASWT) and KRASG12D-mutant cancer cells and demonstrate that G12D-mutant cells exhibit increased viability and reduced ferroptosis upon RSL3 or erastin treatment. These cells show diminished lipid peroxidation and mitochondrial damage, indicating ferroptosis resistance. KRASG12D activates MEK/ERK signaling to phosphorylate LDHA, enhancing glycolysis and lactate production. Exogenous lactate supplementation similarly protects WT cells from ferroptosis. Mechanistically, G12D-mutation-derived lactate induces glutamate-cysteine ligase (GCL) modifier (GCLM) lactylation, a process catalyzed by acetyl-coenzyme A (CoA) acetyltransferase 2 (ACAT2). Inhibition of GCLM lactylation either through the mutation of the lactylation site or by knockdown of ACAT2 diminished the enzymatic activity of GCL and suppressed glutathione synthesis. Importantly, ACAT2 depletion overcomes ferroptosis resistance in KRASG12D-mutant tumors in vivo. Our findings reveal a KRASG12D-driven metabolic adaptation linking GCLM lactylation to ferroptosis resistance, proposing ACAT2 inhibition as a therapeutic strategy for KRAS-mutant cancers.
Item Description:Online verfügbar: 9. Juni 2025, Artikelversion: 9. Juni 2025
Im Titel ist "G12D" hochgestellt
Gesehen am 25.09.2025
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2025.115774

Similar Items