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

  • Cell Chem Biol. 2025 Jun 19;32(6):854-871.e6. doi: 10.1016/j.chembiol.2025.05.004.
Yongliang Liu  1 ,  Hui Hua  2 ,  Yalan Cao  1 ,  Minjing Li  3 ,  Hongying Zhang  1 ,  Shan Du  1 ,  Jieya Liu  1 ,  Ting Luo  4 ,  Yangfu Jiang  5
Affiliations
  • 1. Cancer Center, Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2. Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3. Institute of Integrated Medicine, Binzhou Medical University, Yantai 264003, China.
  • 4. Breast Disease Center, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 5. Cancer Center, Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
PMID: 40472846 DOI: 10.1016/j.chembiol.2025.05.004
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.

Keywords
AKT; BACH1; IRE1α; PTEN; cancer; inositol-requiring enzyme 1α; miR-153; molecular glue; unfolded protein response; verteporfin.
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