PXD078687

PXD078687 is an original dataset announced via ProteomeXchange.

Title	With no lysine kinase 1 in hepatic stellate cells promotes mouse and human liver fibrosis through glycolytic triosephosphate isomerase 1
Description	Liver fibrosis and cirrhosis are major global health burdens with limited treatments. Activated hepatic stellate cells (HSCs) drive fibrosis through increased proliferation, migration, collagen deposition and glycolysis. The aim of this study is to elucidate the signaling events that lead to enhanced glycolysis, subsequent HSC activation, and liver fibrosis. Utilizing a phospho-kinase array, we identified with no lysine kinase 1 (WNK1) as a new kinase in primary human HSCs activated by the pro-fibrotic platelet-derived growth factor-B (PDGF). PDGF-mediated glycolysis in HSCs was attenuated by WNK1 selective inhibitor, WNK-IN-11, as measured by live-cell metabolic assay, Glifon-300 fluorescence, Glucose-Glo assay and glucose transporter 1 immunofluorescence. To understand how WNK1 promotes glycolysis, we employed chemical genetics where an engineered WNK1T301G mutant with a modified ATP pocket accommodated a specific ATP-γ-S analogue to thio-phosphorylate its substrates. Thio-phosphorylated proteins were analyzed by mass spectrometry which identified the glycolytic protein, triosephosphate isomerase 1 (TPI1), as a novel WNK1 direct substrate. TPI1 interacted with WNK1 in condensates, membrane-less phase separation structures. Condensate disruption and knockdown of TPI1 or WNK1 reduced HSC proliferation and migration in vitro. In vivo, pharmacological or genetic WNK1 inhibition significantly attenuated liver fibrosis in carbon tetrachloride and high-fat, choline-deficient, L-amino-acid diet mouse models. Finally, WNK1 inhibition reduced fibrogenesis ex vivo in human precision-cut liver slices. These findings identify WNK1 as a previously unrecognized kinase that promotes HSC activation and liver fibrosis via TPI1-mediated glycolysis, highlighting the WNK1-TPI1 axis as a potential therapeutic target.
HostingRepository	PRIDE
AnnounceDate	2026-08-13
AnnouncementXML	Submission_2026-08-13_04:06:21.689.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Enis Kostallari
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2026-05-21 12:26:58	ID requested
⏵ 1	2026-08-13 04:06:22	announced

Firdaus Z, Khanal S, Washington AM, Solverson JK, Doskey LC, Xiao Y, Yaqubi M, Pereyra D, Heimbach J, Taner T, Krueger EW, Huang CL, Shah VH, Starlinger PP, Razidlo GL, Schellenberg MJ, Kostallari E, With no lysine kinase 1 in hepatic stellate cells promotes mouse and human liver fibrosis through glycolytic triosephosphate isomerase 1. Hepatology, ():(2026) [pubmed]

10.1097/hep.0000000000001833;

submitter keyword: liver fibrosis., chemical genetics,WNK1, glucose metabolism, TPI1, hepatic stellate cells

Enis Kostallari Ph.D.
contact affiliation	ACI in Gastroenterology
contact email	kostallari.enis@mayo.edu
lab head
Enis Kostallari
contact affiliation	Mayo Clinic
contact email	enis.kostallari@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/2026/08/PXD078687

PRIDE project URI

• PRIDE
  1. PXD078687
     1. Label: PRIDE project
     2. Name: With no lysine kinase 1 in hepatic stellate cells promotes mouse and human liver fibrosis through glycolytic triosephosphate isomerase 1