PXD072418-1

PXD072418 is an original dataset announced via ProteomeXchange.

Title	The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents progression of MASLD
Description	Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are leading causes of cirrhosis and hepatocellular carcinoma. Defects in autophagy contribute to the development of MASLD, however, the role of the Unc-51-like autophagy-activating kinase 1 (ULK1) in the pathophysiology of MASLD remains unclear. Herein, we show that ULK1, a serine/threonine kinase and core autophagy protein, is significantly repressed in human MASH livers, and that hepatocyte-specific loss of ULK1, unexpectedly, promotes hepatic steatosis and progression to liver fibrosis, without affecting basal autophagy flux. Phospho-proteomics identified the transcriptional coactivator NCOA3 as a downstream phospho-target of ULK1. Mechanistically, ULK1 phosphorylates NCOA3 to repress its transcriptional activity and restrain the CREB/CBP-mediated de novo lipogenic program. Accordingly, a phosphorylation-deficient NCOA3 mutant drives CREB/CBP-mediated lipogenesis, whereas genetic or pharmacological NCOA3 inhibition prevents steatosis, hepatic inflammation, and profibrotic signaling. Hence, ULK1-mediated NCOA3 phosphorylation is a fundamental and druggable checkpoint against the entire MASLD spectrum.
HostingRepository	PRIDE
AnnounceDate	2026-03-26
AnnouncementXML	Submission_2026-03-26_00:22:00.171.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mehdi Bouhaddou
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	phosphorylated residue
Instrument	timsTOF

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-24 23:08:34	ID requested
⏵ 1	2026-03-26 00:22:00	announced

Dataset with its publication pending

submitter keyword: None

Mehdi Bouhaddou
contact affiliation	Department of Microbiology, Immunology, and Molecular Genetics (MIMG), Quantitative & Computational Biosciences (QCBio), University of California, Los Angeles, LA, USA
contact email	MBouhaddou@mednet.ucla.edu
lab head
Mehdi Bouhaddou
contact affiliation	UCLA
contact email	bouhaddoulab@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/03/PXD072418

PRIDE project URI

• PRIDE
  1. PXD072418
     1. Label: PRIDE project
     2. Name: The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents progression of MASLD