PXD064881

PXD064881 is an original dataset announced via ProteomeXchange.

Title	Repurposing BCL2 inhibitors: Venetoclax protects against acinar cell necrosis in acute pancreatitis by promoting apoptosis
Description	Acute pancreatitis (AP), a severe inflammatory disorder of the pancreas, lacks effective pharmacological treatment. The disease is primarily driven by necrosis of pancreatic acinar cells (PACs), which intensifies inflammation and organ injury. This study explores the potential of BCL2 inhibitors, specifically Navitoclax and Venetoclax, to shift cell death pathways from necrosis to apoptosis and thereby mitigate disease severity. Ex vivo models using cerulein or ethanol/palmitoleic acid (EtOH/POA) showed that both inhibitors significantly reduced necrosis, increased apoptosis, and improved PAC viability and ATP levels. In mouse models of AP, both drugs promoted apoptosis and decreased tissue necrosis, with Venetoclax showing superior efficacy and safety. Venetoclax markedly reduced disease severity in two AP models without affecting healthy tissue or inducing thrombocytopenia. In contrast, Navitoclax caused apoptosis even in healthy tissue and triggered thrombocytopenia. Importantly, both drugs attenuated pathological Ca2+ responses in PACs and upregulated the expression of Ca²⁺-binding proteins S100A8/A9 and the chemokine CCL8. The latter may mediate enhanced apoptotic clearance and limit secondary necrosis, supporting the therapeutic shift from necrosis to apoptosis. Proteomic analyses revealed extensive drug-induced remodeling. In the short-term AP model, both inhibitors altered expression of proteins linked to intracellular compartments and extracellular signaling, reflecting cellular adaptation. In CP, Navitoclax strongly upregulated ECM and lysosomal proteins while downregulating ribosomal components – indicating intensified fibrosis and suppressed protein synthesis. Venetoclax had milder effects and did not worsen fibrosis. Despite Navitoclax’s efficacy toward activated pancreatic stellate cells in vitro, it exacerbated fibrosis and tissue atrophy in CP in vivo, likely due to ongoing parenchymal damage and stellate cell activation. Together, these findings demonstrate that selective BCL2 inhibition with Venetoclax promotes apoptosis, reduces necrosis, and improves outcomes in AP, supporting its repurposing as a therapeutic strategy. However, BCL2 inhibition does not benefit CP and may aggravate fibrosis, underscoring the need for context-specific approaches.
HostingRepository	PRIDE
AnnounceDate	2025-08-04
AnnouncementXML	Submission_2025-08-03_22:35:35.802.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Urszula Jankowska
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-11 07:05:17	ID requested
⏵ 1	2025-08-03 22:35:36	announced

Litewka JJ, Szopa MD, Fryt K, Jakubowska MA, Jankowska U, Skupien-Rabian B, Hajduk K, Werner E, Stopa KB, Kusiak AA, Krzysztofik D, Madeja Z, Ferdek PE, Repurposing BCL2 inhibitors: Venetoclax protects against acinar cell necrosis in acute pancreatitis by promoting apoptosis. Cell Death Dis, 16(1):566(2025) [pubmed]

10.1038/s41419-025-07881-w;

submitter keyword: pancreas, BCL2 inhibitors, Venetoclax,Pancreatitis, ABT-199, calcium signaling, fibrosis, ABT-263, necrosis, Navitoclax, apoptosis

Pawel Ferdek
contact affiliation	Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Poland
contact email	pawel.ferdek@uj.edu.pl
lab head
Urszula Jankowska
contact affiliation	Proteomics and Mass Spectrometry Core Facility, Malopolska Centre of Biotechnology, Jagiellonian University
contact email	urszula.jankowska@uj.edu.pl
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/2025/08/PXD064881

PRIDE project URI

• PRIDE
  1. PXD064881
     1. Label: PRIDE project
     2. Name: Repurposing BCL2 inhibitors: Venetoclax protects against acinar cell necrosis in acute pancreatitis by promoting apoptosis