PXD071546-1

PXD071546 is an original dataset announced via ProteomeXchange.

Title	A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis
Description	Endoplasmic reticulum-associated degradation (ERAD) is a critical protein quality control mechanism that also regulates lipid metabolism and calcium homeostasis. Dysregulation of ERAD and unfolded protein response underlies diseases including cancer, neurodegenerative disorders, and metabolic syndromes. Small molecule modulators of ERAD could enable mechanistic discovery and therapeutic intervention, but few have been identified. Using a high-content screening, we discovered several ERAD-modulating compounds, including NCATS-SM0225, an ERAD inhibitor that unexpectedly binds all three isoforms of VDAC, outer mitochondrial membrane proteins enriched at mitochondria-associated membranes. This led us to discover an essential role for VDACs in ERAD and ER-phagy. NCATS-SM0225 elevates cytosolic, ER, and mitochondrial calcium through calcium influx and IP3R–MCU activity. This calcium imbalance strengthens VDAC1–IP3R coupling and activates PERK, which phosphorylates STIM1 and drives degradation of key ERAD regulators. Loss of these components amplifies PERK signaling and selectively kills cancer cells while sparing normal cells. These findings uncover a cancer-specific role of VDACs in ERAD regulation and calcium signaling, highlighting a therapeutically actionable vulnerability.
HostingRepository	PRIDE
AnnounceDate	2026-01-20
AnnouncementXML	Submission_2026-01-20_11:51:47.382.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD071546
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Dingyin Tao
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-03 15:46:58	ID requested
⏵ 1	2026-01-20 11:51:48	announced

Yan W, Talley DC, Syam A, Danchik C, Zhong Y, Zhang X, Liu X, Baljinnyam B, Kales SC, Cyr MG, Fang Y, Zakharov AV, Hu X, Niehoff T, Xu T, Qu Y, Yang A, Courouble VV, Yao Q, Simeonov A, Huang R, Rostovtseva TK, Bezrukov SM, LeClair CA, Egan JM, Wang H, Tao D, Rai G, Henderson MJ, Fang S, A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis. Nat Commun, 17(1):1058(2026) [pubmed]

10.6019/PXD071546;

10.1038/s41467-025-67816-z;

submitter keyword: ERAD, proteomics, ingel digestion, ER-phagy, VDAC

Dingyin Tao
contact affiliation	National Center for Advancing Translational Sciences, National Institutes of Health
contact email	dingyin.tao@nih.gov
lab head
Dingyin Tao
contact affiliation	National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS)
contact email	dingyin.tao@nih.gov
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD071546
     1. Label: PRIDE project
     2. Name: A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis