PXD062451

PXD062451 is an original dataset announced via ProteomeXchange.

Title	GCLM lactylation mediated by ACAT2 promotes ferroptosis resistance in KRASG12D-mutant cancer
Description	KRAS mutation activates multiple intracellular signalling pathways, leading to tumour development and progression. However, whether KRAS mutations are involved in regulating ferroptosis in cancer and the underlying mechanism remains unclear. Here, we constructed stable KRASWT and KRASG12D-mutant cell lines by transfecting wild-type (WT) or G12D plasmids into original KRAS WT cells and detected their cell viability under the treatment of ferroptosis inducer RSL3 or erastin. We found compared with WT cells, KRASG12D-mutated pancreatic and colorectal cancer cells presented greater viability and less cell death, along with lower levels of lipid peroxidation (LPO) and fewer damaged mitochondria, suggesting that the G12D mutation confers resistance to ferroptosis. Moreover, we found that KRASG12D mutated cancer cells demonstrated increased glycolysis and elevated lactate production, which was dependent on MEK-ERK-mediated L-lactate dehydrogenase A (LDHA) phosphorylation. Importantly, lactate supplementation in WT cells also resulted in ferroptosis resistance, indicating that G12D mutation-induced resistance to ferroptosis may be linked to lactate production. Mechanistically, G12D mutation-derived lactate accumulation induces Glutamate-cysteine ligase modifier (GCLM) lactylation, a process catalysed by Acetyl-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 Glutamate-cysteine ligase (GCL) and suppressed Glutathione (GSH) synthesis. Ultimately, we found that ACAT2 knockdown can overcomes ferroptosis resistance in G12D-mutated cancer models in vivo. Thus, our study reveals a novel role for the G12D mutation in regulating GCLM lactylation and ferroptosis. Targeting GCLM lactylation may represent a promising strategy for overcoming ferroptosis resistance.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-06_17:23:25.491.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Shiye Ruan
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	lactic acid
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-01 02:48:23	ID requested
⏵ 1	2025-05-06 17:23:25	announced

Dataset with its publication pending

submitter keyword: KRASG12D-mutant,lactylation, PDAC

Chuanzhao Zhang
contact affiliation	Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
contact email	Zhangchuanzhao@gdph.org.cn
lab head
Shiye Ruan
contact affiliation	Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University
contact email	ruanshiye@gdph.org.cn
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD062451
     1. Label: PRIDE project
     2. Name: GCLM lactylation mediated by ACAT2 promotes ferroptosis resistance in KRASG12D-mutant cancer