Journal Article

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

Zhang, Xianzheng, Simeonov, Anton, Fang, Shengyun, Henderson, Mark J., Yan, Wenjing, Zhong, Yongwang, Cyr, Matthew G., LeClair, Christopher A., Fang, Yuhong, Tao, Dingyin, Kales, Stephen C., Liu, Xiaoying, Talley, Daniel C., Zakharov, Alexey V., Rai, Ganesha, Danchik, Carina, Syam, Antara, Wang, Hua, Hu, Xin, Baljinnyam, Bolormaa, Rostovtseva, Tatiana K., Niehoff, Taylor, Courouble, Valentine V., Yang, Allison, Qu, Yanyan, Yao, Qin, Huang, Ruili, Bezrukov, Sergey M., Xu, Tuan, Egan, Josephine M.

2026

Overview

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. Here the authors present NCATS-SM0225, a small molecule that inhibits ERAD and selectively kills cancer cells by binding VDACs, disrupting calcium homeostasis, and triggering the PERK-STIM1 pathway to degrade ERAD regulators.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/109 / 13/2 / 13/89 / 14/63 / 38/23 / 38/35 / 38/47 / 38/88 / 49/109 / 49/98 / 631/80/474/2287 / 631/80/642/1463 / 631/92/555 / 64/60 / Animals / Calcium / Calcium (mitochondrial) / Calcium (reticular) / Calcium - metabolism / Calcium homeostasis / Calcium influx / Calcium Signaling - drug effects / Calcium signalling / Cancer / Cell death / Cell Death - drug effects / Cell Line, Tumor / Degradation / Disruption / Endoplasmic reticulum / Endoplasmic Reticulum - drug effects / Endoplasmic Reticulum - metabolism / Endoplasmic Reticulum-Associated Degradation - drug effects / Homeostasis / Homeostasis - drug effects / Humanities and Social Sciences / Humans / Inositol 1,4,5-trisphosphate receptors / Inositol 1,4,5-Trisphosphate Receptors - metabolism / Isoforms / Ligands / Lipid metabolism / Lipids / Membrane proteins / Membranes / Metabolic disorders / Metabolic syndrome / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / multidisciplinary / Neoplasm Proteins - metabolism / Neoplasms - drug therapy / Neoplasms - metabolism / Neoplasms - pathology / Neurodegenerative diseases / Neuromodulation / Protein folding / Proteins / Quality control / Science / Science (multidisciplinary) / Small Molecule Libraries - pharmacology / STIM1 protein / Stromal Interaction Molecule 1 - metabolism / Voltage-Dependent Anion Channel 1 - metabolism