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Pharmacological Inhibition of SLC33A1 Promotes Endoplasmic Reticulum Hyperoxidation and Induces Adaptive IRE1/XBP1s
Sergei Kutseikin1, Maria Rafiq2,3, Prerona Bora1,3
1Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA.
Biorxiv : the Preprint Server for Biology
|February 27, 2026
Summary
The small molecule IXA4 inhibits the ER transporter SLC33A1, impacting ER redox homeostasis. This discovery offers a new therapeutic strategy for diseases like lung cancer by targeting SLC33A1.
Area of Science:
- Biochemistry
- Molecular Biology
- Cellular Biology
Background:
- The endoplasmic reticulum (ER) transporter SLC33A1 is a potential therapeutic target for various diseases.
- Currently, no specific pharmacologic modulators for SLC33A1 exist.
Purpose of the Study:
- To identify and characterize pharmacologic modulators of SLC33A1.
- To investigate the role of SLC33A1 in cellular signaling and homeostasis.
- To explore the therapeutic potential of SLC33A1 inhibition.
Main Methods:
- Small molecule screening and characterization (IXA4).
- Genetic manipulation (SLC33A1 depletion).
- Chemoproteomic analysis and cryo-electron microscopy.
- Cell viability assays.
Main Results:
- IXA4 selectively binds and inhibits SLC33A1 activity.
- SLC33A1 inhibition leads to ER lumen hyperoxidation and activation of IRE1/XBP1s signaling.
- IXA4 treatment selectively reduces viability in KEAP1-deficient lung adenocarcinoma cells.
- Genetic SLC33A1 depletion phenocopies IXA4 effects.
Conclusions:
- SLC33A1 plays a crucial role in regulating ER redox homeostasis.
- IXA4 is a novel pharmacologic inhibitor of SLC33A1.
- Targeting SLC33A1 with IXA4 presents a potential therapeutic avenue for specific cancers and other diseases.
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