Evidence map›Paper›PMID 41547848›Full record

ArticleNature communications2026

A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis.

Wenjing Yan, Daniel C Talley, Antara Syam, Carina Danchik, Yongwang Zhong, Xianzheng Zhang, Xiaoying Liu, Bolormaa Baljinnyam, Stephen C Kales, Matthew G Cyr and 20 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Review
  3. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

30 authors.

Wenjing YanDepartment of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
Daniel C TalleyNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Antara SyamEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.ORCID http://orcid.org/0009-0004-4974-0357
Carina DanchikNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Yongwang ZhongDepartment of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
Xianzheng ZhangSchool of Pharmacy and Science, Anhui Medical University, Hefei, P. R. China.
Xiaoying LiuSchool of life sciences, Anhui medical university, Hefei, P. R. China.ORCID http://orcid.org/0000-0003-3450-5683
Bolormaa BaljinnyamNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.ORCID http://orcid.org/0000-0001-9548-4965
Stephen C KalesNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Matthew G CyrNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Yuhong FangNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Alexey V ZakharovNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.ORCID http://orcid.org/0000-0003-2466-1711
Xin HuNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Taylor NiehoffNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.ORCID http://orcid.org/0000-0002-0506-6012
Tuan XuNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.ORCID http://orcid.org/0000-0001-6430-3500
Yanyan QuNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Allison YangNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Valentine V CouroubleNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Qin YaoLaboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, USA.
Anton SimeonovNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Ruili HuangNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Tatiana K RostovtsevaEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.ORCID http://orcid.org/0000-0001-7299-7362
Sergey M BezrukovEunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
Christopher A LeClairNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.ORCID http://orcid.org/0000-0002-2746-5938
Josephine M EganLaboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-8945-0053
Hua WangDepartment of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, P. R. China.ORCID http://orcid.org/0000-0002-2605-5697
Dingyin TaoNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA. dingyin.tao@nih.gov.ORCID http://orcid.org/0000-0001-6531-2740
Ganesha RaiNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA. bantukallug@mail.nih.gov.
Mark J HendersonNational Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA. mark.henderson2@nih.gov.ORCID http://orcid.org/0000-0001-8590-7338
Shengyun FangDepartment of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA. sfang@som.umaryland.edu.ORCID http://orcid.org/0000-0001-7280-5463

Funding

Pharmacologic enhancement of UBA1 activity in models of VEXAS syndromeU01AR081599 · UNIVERSITY OF MARYLAND BALTIMORE · 2025 to 2025
$355k
NIAMS NIH HHS U01 AR081599U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 5U01AR081599
6 · The paper itself

Abstract

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.

Indexed as

CalciumEndoplasmic Reticulum-Associated DegradationNeoplasmsVoltage-Dependent Anion ChannelsAnimalsCalcium SignalingCell DeathCell Line, TumorEndoplasmic ReticulumHomeostasisHumansInositol 1,4,5-Trisphosphate ReceptorsLigandsMitochondriaMitochondria Associated MembranesCalciumInositol 1,4,5-Trisphosphate ReceptorsLigandsVoltage-Dependent Anion Channels

Identifiers

PMID41547848
PMCPMC12847789

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.