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

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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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Dingyin Tao

LAB HEAD: Dingyin Tao

PROVIDER: PXD071546 | Pride | 2026-01-20

REPOSITORIES: Pride

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

Yan Wenjing W Talley Daniel C DC Syam Antara A Danchik Carina C Zhong Yongwang Y Zhang Xianzheng X Liu Xiaoying X Baljinnyam Bolormaa B Kales Stephen C SC Cyr Matthew G MG Fang Yuhong Y Zakharov Alexey V AV Hu Xin X Niehoff Taylor T Xu Tuan T Qu Yanyan Y Yang Allison A Courouble Valentine V VV Yao Qin Q Simeonov Anton A Huang Ruili R Rostovtseva Tatiana K TK Bezrukov Sergey M SM LeClair Christopher A CA Egan Josephine M JM Wang Hua H Tao Dingyin D Rai Ganesha G Henderson Mark J MJ Fang Shengyun S

Nature communications 20260117

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-modulat ...[more]

PMID: 41547848

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Project description:1H NMR is used to detect alterations in metabolites and their linkage to metabolic processes in a number of pathological conditions including breast cancer. Inositol 1, 4, 5 trisphosphate (IP3R) receptor is an intracellular calcium channel known to regulate metabolism and cellular bioenergetics. Its expression is up regulated in a number of cancers. However, its linkage to metabolism in disease conditions has not been evaluated. This study was designed to determine the association if any, of these metabolites with altered expression of IP3R in breast cancer. We used 1H NMR to identify metabolites in the serum of breast cancer patients (n = 27) and performed Real-time Polymerase Chain Reaction analysis for quantifying the expression of IP3R type 3 and type 2 in tissues from breast cancer patients (n = 40). Principal Component Analysis (PCA) and Partial Least Square-Discriminant Analysis (PLS-DA) clearly distinguished patients with high/low IP3R expression from healthy subjects. The present study revealed high expression of IP3R type 2 and type 3 in human breast tumor tissue compared to adjacent non-tumorous tissue. Moreover, patients with = 2-fold increase in IP3R (high IP3R group) had significantly higher concentration of metabolic intermediates compared to those with < 2-fold increase in IP3R (low IP3R group). We observed an increase in lipoprotein content and the levels of metabolites like lactate, lysine and alanine and a decrease in the levels of pyruvate and glucose in serum of high IP3R group patients when compared to those in healthy subjects. Receiver operating characteristic (ROC) curve analysis was performed to show the clinical utility of metabolites. In addition to the human studies, functional relevance of IP3Rs in causing metabolic disruption was observed in MCF-7 and MDA MB-231 cells. Results from our studies bring forth the importance of metabolic (or metabolomics) profiling of serum by 1H NMR in conjunction with tissue expression studies for characterizing breast cancer patients. The results from this study provide new insights into relationship of breast cancer metabolites with IP3R.

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	225C1_18KDa_3ul.raw	Raw
	225C1_35KDa_3ul.raw	Raw
	225C2_35KDa_3ul.raw	Raw
	ShengyunCP60IngelFeb2023.mzML	Mzml
	ShengyunCP60IngelFeb2023.mzid	Mzid