PXD079803-1

PXD079803 is an original dataset announced via ProteomeXchange.

Title	Pharmacological Destabilization of ZEB2 Attenuates Atherosclerosis via Restoration of Lipid Catabolism
Description	he pathogenesis of atherosclerosis involves phenotypic reprogramming of vascular smooth muscle cells (VSMCs) coupled with profound lipid metabolic dysfunction; however, the critical transcriptional regulators governing this process remain incompletely understood. Here, we identify zinc finger E-box binding homeobox 2 (ZEB2) as a central regulator linking VSMC phenotypic switching to lipid dysregulation in atherosclerosis. Single-cell transcriptomic trajectory analyses revealed progressive induction of ZEB2 during the transition of contractile VSMCs toward foam-like states, a finding validated in both murine and human atherosclerotic plaques. Genetic and pharmacological inhibition of ZEB2 markedly reduced lipid accumulation in VSMCs and attenuated atherosclerotic lesion burden while improving plaque composition in vivo. Next, we found ZEB2 suppressed fatty acid oxidation programs by transcriptionally repressing melanocortin 2 receptor (Mc2r), thereby limiting Mc2r–cAMP signaling and downstream lipid catabolic gene expression. We further developed TB15, a novel small molecule that selectively destabilizes ZEB2 protein by promoting deacetylation-dependent ubiquitination and proteasomal degradation without affecting ZEB2 transcription. To enable precision therapy, an RGD-functionalized mesoporous polydopamine nanoparticle delivery system was engineered to target phenotypically transformed VSMCs within atherosclerotic plaques, achieving superior therapeutic efficacy with minimal systemic toxicity. Notably, machine learning–based drug response modeling (BFReg-NN) predicted optimal anti-atherosclerotic efficacy when TB15 was combined with fluvastatin or pitavastatin, nominating a rational combination strategy. Together, this work defines the ZEB2-Mc2r axis in atherosclerosis, presents a first in class ZEB2 degrader, and demonstrates a targeted nanotherapeutic approach with strong translational potential for precision treatment of atherosclerotic disease.
HostingRepository	iProX
AnnounceDate	2026-06-16
AnnouncementXML	Submission_2026-06-17_01:33:16.997.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Lingdan Zhao
SpeciesList	scientific name: Rattus norvegicus; NCBI TaxID: 10116;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2026-06-17 01:30:00	ID requested
⏵ 1	2026-06-17 01:33:17	announced

Dataset with its publication pending

submitter keyword: ZEB2, lipid, atherosclerosis, TB15, nanoparticles

Bin Zheng
contact affiliation	Hebei Medical University
contact email	doublezb@hebmu.edu.cn
lab head
Lingdan Zhao
contact affiliation	Hebei Medical University
contact email	15226552138@163.com
dataset submitter

iProX dataset URI