ArticleNature communications2022
Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 105 citations in OpenAlex.
- Translating the Crosstalk Between Unfolded Protein Response and Ferroptosis to Cancer Therapies.Current oncology reports · 2026Review
- Targeting the IRE1α/XBP1 pathway in type 2 diabetes mellitus: from ER stress signaling to therapeutic opportunity.Molecular biology reports · 2026Review
- Unconventional role of hydroxymethylglutaryl-CoA synthase 1 in driving pathogenic TScience advances · 2026Article
- mTOR signaling contributes to system-driven rhythmic gene expression in mouse liver.Science advances · 2026Article
- Needle-Knife Therapy Relieves Inflammation and Neuronal Apoptosis in Cervical Spondylotic Radiculopathy via IRE1α-XBP1 Signaling.Global spine journal · 2026Article
- Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy.Signal transduction and targeted therapy · 2026Review
- Pharmacological Inhibition of SLC33A1 Promotes Endoplasmic Reticulum Hyperoxidation and Induces Adaptive IRE1/XBP1s Signaling.bioRxiv : the preprint server for biology · 2026Article
- Targeting the UPR with Small Molecules: Emerging Strategies for Immune Regulation.Molecules (Basel, Switzerland) · 2026Review
- The Role of Crosstalk Between the Unfolded Protein Response and Autophagy in Diseases Associated with Sympathetic Nervous System Imbalance: Mechanisms and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Adaptive inter-tissue proteostasis networks in aging and neurodegeneration.Bioscience reports · 2026Review
- Improving Proteostasis of Trafficking-Deficient GABAACS chemical neuroscience · 2025Article
- Drug repurposing screen identifies an HRI activating compound that promotes adaptive mitochondrial remodeling in MFN2-deficient cells.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Kirenol relieves rheumatoid arthritis by targeting the TWEAK/Fn14 pathway.International journal of molecular medicine · 2025Article
- Harnessing indole scaffolds to identify small-molecule IRE1α inhibitors modulating XBP1 mRNA splicing.Nature communications · 2025Article
- Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells.Nature reviews. Endocrinology · 2025Review
- Review
- Optogenetic Clustering of Human IRE1 Reveals Differential Regulation of Transcription and mRNA Splice Isoform Abundance by the UPR.bioRxiv : the preprint server for biology · 2025Article
- Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells.bioRxiv : the preprint server for biology · 2025Article
- Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B.Brain : a journal of neurology · 2025Article
- Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling.Cancer research · 2025Article
9 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
In obesity, signaling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects. Overexpression of the IRE1-regulated transcription factor XBP1s in liver or fat protects against obesity-linked metabolic deterioration. However, hyperactivation of IRE1 engages regulated IRE1-dependent decay (RIDD) and TRAF2/JNK pro-inflammatory signaling, which accelerate metabolic dysfunction. These pathologic IRE1-regulated processes have hindered efforts to pharmacologically harness the protective benefits of IRE1/XBP1s signaling in obesity-linked conditions. Here, we report the effects of a XBP1s-selective pharmacological IRE1 activator, IXA4, in diet-induced obese (DIO) mice. IXA4 transiently activates protective IRE1/XBP1s signaling in liver without inducing RIDD or TRAF2/JNK signaling. IXA4 treatment improves systemic glucose metabolism and liver insulin action through IRE1-dependent remodeling of the hepatic transcriptome that reduces glucose production and steatosis. IXA4-stimulated IRE1 activation also enhances pancreatic function. Our findings indicate that systemic, transient activation of IRE1/XBP1s signaling engenders multi-tissue benefits that integrate to mitigate obesity-driven metabolic dysfunction.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.