PXD068220-1

PXD068220 is an original dataset announced via ProteomeXchange.

Title	Integrating proteomics and metabolomics to reveal MAT2A for metabolic reprogramming and relative combination strategies in non-small cell lung cancer
Description	MAT2A, a key enzyme in the methionine cycle, generates S-adenosylmethionine (SAM), a critical metabolite involved in multiple metabolic pathways and epigenetic regulation. Although MAT2A is frequently overexpressed in tumors, its role in metabolic reprogramming within non-small cell lung cancer (NSCLC) remains poorly understood. Current MAT2A inhibitors, such as AG270, exhibit limited efficacy and are primarily used in MTAP-deleted tumors, highlighting the need to explore additional therapeutic strategies. Here, we employed proteomics and untargeted metabolomics in NSCLC cell lines, complemented by targeted metabolomics, RT-qPCR and ATAC-seq, to systematically characterize MAT2A-rewired metabolic reprogramming and identify potential combination treatment strategies. Totally, MAT2A knockdown or inhibition significantly disrupted fatty acid biosynthesis, cholesterol homeostasis, glycolysis and the transsulfuration pathways. In lipid metabolism, MAT2A inhibition impaired cell proliferation by suppressing fatty acid biosynthesis, and induced cholesterol biosynthesis and efflux impairment. Combining MAT2A inhibitors with the liver X receptor agonist LXR-623, which facilitated cholesterol efflux, effectively depleted intracellular cholesterol and augmented anti-tumor efficacy. In energy metabolism, MAT2A mainly inhibited glycolysis through HIF1A regulation and GLUT1 inhibitor BAY-876 demonstrated a synergetic effect when combined with AG270. In the transsulfuration pathway, MAT2A transcriptionally regulated a key enzyme CBS, and combination treatments using AG270 with either the SLC7A11 inhibitor HG106 or the PHGDH inhibitor NCT-503 exhibited enhanced anti-tumor activity. Overall, our findings identified MAT2A as a critical regulator of metabolic networks in NSCLC and propose several rational combination therapies to enhance MAT2A inhibitor efficacy.
HostingRepository	iProX
AnnounceDate	2025-09-09
AnnouncementXML	Submission_2026-04-08_00:19:10.072.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yimin Chen
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF; timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-09 02:26:24	ID requested
⏵ 1	2026-04-08 00:19:10	announced

Dataset with its publication pending

submitter keyword: MAT2A, non-small cell lung cancer, proteomics, metabolomics, metabolic reprogramming

Hu Zhou
contact affiliation	Shanghai Institute of Materia Medica, Chinese Academy of Sciences
contact email	zhouhu@simm.ac.cn
lab head
Yimin Chen
contact affiliation	Shanghai Institute of Materia Medica, Chinese Academy of Sciences
contact email	chenyimin@simm.ac.cn
dataset submitter

iProX dataset URI