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Cell Chemical Biology

Cell Chemical Biology

IF: 7.2
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Mechanism by which the molecular glue-like verteporfin induces IRE1α dimerization and activation to synergize with AKT inhibition in breast cancer

Published:19 June 2025 DOI: 10.1016/j.chembiol.2025.05.004
Yongliang Liu , Hui Hua , Yalan Cao , Minjing Li , Hongying Zhang , Shan Du , Jieya Liu , Ting Luo , Yangfu Jiang

Abstract

Inositol-requiring enzyme 1α (IRE1α) signaling is one of three arms of the unfolded protein response, playing a vital role in maintaining endoplasmic reticulum homeostasis. Pharmacological modulation of this pathway offers potential therapeutic strategies for various diseases. Molecular glues may regulate protein stability and activity by inducing protein-protein interaction. Here, we find that verteporfin functions as a molecular glue, promoting IRE1α dimerization and activation. Specifically, verteporfin binds to IRE1α, facilitating its dimerization, which relies on the His692 residue. This activation of IRE1α triggers XBP1 splicing and miR-153-mediated downregulation of PTEN, along with AKT phosphorylation. Additionally, we identify the pro-metastasis gene BACH1 as a novel target of miR-153, which is downregulated by IRE1α and verteporfin. While verteporfin inhibits breast cancer cell viability and invasion, its combination with an AKT inhibitor synergistically suppresses breast cancer progression. Our findings establish a mechanistic link between IRE1α and PI3K/AKT signaling, highlighting a possibility for therapeutic intervention.

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Materials
Procduct Name CAS Molecular Formula Supplier Price
MG-132 133407-82-6 C26H41N3O5 428 suppliers $11.00-$9807.90
MG-132 133407-82-6 C26H41N3O5 428 suppliers $11.00-$9807.90
MG-132 133407-82-6 C26H41N3O5 428 suppliers $11.00-$9807.90
MG-132 133407-82-6 C26H41N3O5 428 suppliers $11.00-$9807.90
BAFILOMYCIN A1 88899-55-2 C35H58O9 307 suppliers $80.00-$7612.00
BAFILOMYCIN A1 88899-55-2 C35H58O9 307 suppliers $80.00-$7612.00
BAFILOMYCIN A1 88899-55-2 C35H58O9 307 suppliers $80.00-$7612.00
BAFILOMYCIN A1 88899-55-2 C35H58O9 307 suppliers $80.00-$7612.00
Protoporphyrin IX 553-12-8 C34H34N4O4 275 suppliers $24.00-$4721.00
Protoporphyrin IX 553-12-8 C34H34N4O4 275 suppliers $24.00-$4721.00

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