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

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

  • Nat Commun. 2026 Jan 17;17(1):1058. doi: 10.1038/s41467-025-67816-z.
Wenjing Yan 1,  Daniel C Talley 2,  Antara Syam 3 4,  Carina Danchik 2,  Yongwang Zhong 1,  Xianzheng Zhang 5,  Xiaoying Liu 6,  Bolormaa Baljinnyam 2,  Stephen C Kales 2,  Matthew G Cyr 2,  Yuhong Fang 2,  Alexey V Zakharov 2,  Xin Hu 2,  Taylor Niehoff 2,  Tuan Xu 2,  Yanyan Qu 2,  Allison Yang 2,  Valentine V Courouble 2,  Qin Yao 7,  Anton Simeonov 2,  Ruili Huang 2,  Tatiana K Rostovtseva 3,  Sergey M Bezrukov 3,  Christopher A LeClair 2,  Josephine M Egan 7,  Hua Wang 8,  Dingyin Tao 9,  Ganesha Rai 10,  Mark J Henderson 11,  Shengyun Fang 12 13
Affiliations

Affiliations

  • 1 Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
  • 2 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
  • 3 Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
  • 4 The Catholic University of America, Washington, DC, USA.
  • 5 School of Pharmacy and Science, Anhui Medical University, Hefei, P. R. China.
  • 6 School of life sciences, Anhui medical university, Hefei, P. R. China.
  • 7 Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, USA.
  • 8 Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, P. R. China.
  • 9 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA. [email protected].
  • 10 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA. [email protected].
  • 11 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA. [email protected].
  • 12 Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA. [email protected].
  • 13 Program in Oncology, UM Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. [email protected].
PMID: 41547848 DOI: 10.1038/s41467-025-67816-z
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.

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