bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–02–15
seven papers selected by
Susan Logue, University of Manitoba
  1. Heritable ER stress impairs mitochondrial metabolism and maintenance of hematopoietic stem cells after low-dose irradiation.
  2. An integrated framework identified potent inhibitors targeting IRE1α.
  3. The endoplasmic reticulum stress-regulated XBP1s transcription factor drives a negative feedback loop on FLT3 expression in leukemia cells.
  4. Endothelial IRE1 signaling maintains blood-brain barrier integrity and limits neuroinflammation after traumatic brain injury.
  5. Targeting the UPR with Small Molecules: Emerging Strategies for Immune Regulation.
  6. Unfolded Protein Response as a Therapeutic Target: 4-(Heptyloxy)phenol Induces Programmed Cell Death in Ewing Sarcoma.
  7. Triglycerides induce endoplasmic reticulum lipid bilayer stress to activate PERK and enhance antifungal immunity.
  1. iScience. 2026 Feb 20. 29(2): 114738
    Heritable ER stress impairs mitochondrial metabolism and maintenance of hematopoietic stem cells after low-dose irradiation.
    Stephanie G Moreno, Federica Ferri, Daniel Lewandowski, Vilma Barroca, Saiyiramii Devanand, Nathalie Dechamps, Paul-Henri Romeo, Nathalie Gault.
      How hematopoietic stem cells (HSCs) respond to low doses of radiation currently used in medicine is largely unknown. Here, we show that HSC exposed to a single 20 mGy dose of irradiation (20 mGy-HSC) exhibit, when proliferating, oxidative stress and altered metabolism associated with increased mitochondrial reactive oxygen species and mitochondrial Ca2+ overload. These mitochondrial defects arise from immediate and sustained endoplasmic reticulum (ER) stress, induced by proliferative 20 mGy-HSC through the activation of the eIF2α-ATF4 branch of the unfolded protein response (UPR). The ER stress is heritable and leads, in long-term quiescent 20 mGy-HSC, to the activation of the IRE1α-Xbp1 branch of UPR, which fails to restore ER homeostasis, resulting in a decreased long-term HSC pool. Finally, we show that this heritable ER stress leads to global DNA hypomethylation, partially reversed by the early inhibition of ER stress. Our studies illuminate how adaptive ER stress responses can lead to mitochondrial defects and HSC dysfunctions.
    Keywords:  Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2026.114738
  2. Bioorg Med Chem. 2026 Feb 07. pii: S0968-0896(26)00046-5. [Epub ahead of print]136 118590
    An integrated framework identified potent inhibitors targeting IRE1α.
    Subramaniyan Divya, Priti Talwar, Palaniyandi Ravanan.
      Inositol-requiring enzyme 1 (IRE1α) is one of the key sensors and signaling effectors of the unfolded protein response (UPR), which is essential for preserving endoplasmic reticulum (ER) homeostasis. Dysregulation of IRE1α signaling can lead to several illnesses. Initially, we employed the multidocking approach utilizing AutoDock Vina, AutoDock Wizard, and iGEMDOCK to predict the accurate binding affinities of the flavonoid library against IRE1α and rank them based on their affinities. Subsequently, post-docking approaches were used to refine the hit selection. Finally, the top-ranked flavonoids were selected based on their consistent high binding affinity and exhibited strong binding within the ATP-binding pocket of the kinase active site. In vitro kinase assays revealed that both amentoflavone and glycitein significantly inhibited IRE1α kinase activity, with IC50 values of 16.4 μM and 23.68 μM, respectively. Cell-based studies demonstrated that these flavonoids have anti-inflammatory properties and significantly promote robust activation of XBP1 splicing and IRE1α expression under normal conditions. In contrast, flavonoid pretreatment significantly attenuated LPS-induced IRE1α-XBP1 signaling and reduced inflammatory responses. Overall, our results indicate that both glycitein and amentoflavone exhibit promising modulatory effects on IRE1α. To the best of our knowledge, this is the first study to report the modulatory potential of flavonoids amentoflavone and glycitein to possess both IRE1α kinase inhibitory and RNase-activating properties. This work provides a valuable basis for the development of flavonoid-based IRE1α inhibitors to treat ER stress and associated inflammatory diseases.
    Keywords:  Flavonoids; IRE1α modulators; Post-docking approaches
    DOI:  https://doi.org/10.1016/j.bmc.2026.118590
  3. Cancer Lett. 2026 Feb 10. pii: S0304-3835(26)00073-X. [Epub ahead of print] 218310
    The endoplasmic reticulum stress-regulated XBP1s transcription factor drives a negative feedback loop on FLT3 expression in leukemia cells.
    Céline Philippe, Manon Jaud, Clara Da Cunha, Loïc Van Den Berghe, Manon Farce, Marina Bousquet, Stéphane Pyronnet, Laurent Mazzolini, Christian Touriol.
      
    Keywords:  Acute Myeloid Leukemia; ER Stress; FLT3 (Fms-Like Tyrosine kinase 3); FLT3-ITD; IRE1/XBP1 axis
    DOI:  https://doi.org/10.1016/j.canlet.2026.218310
  4. Cell Death Dis. 2026 Feb 09.
    Endothelial IRE1 signaling maintains blood-brain barrier integrity and limits neuroinflammation after traumatic brain injury.
    Qiyan Fan, Mika Takarada-Iemata, Takashi Tanaka, Loc Dinh Nguyen, Nahoko Okitani, RongRong Yang, Takashi Tamatani, Hiroshi Ishii, Tsuyoshi Hattori, Hiroyasu Kidoya, Yoshiaki Kubota, Takao Iwawaki, Osamu Hori.
      Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) contribute to the pathogenesis of traumatic brain injury (TBI), yet the cell type-specific roles of UPR pathways remain poorly understood. We previously identified endothelial cells (ECs) as a primary site of IRE1 pathway activation following brain injury. In this study, we investigated the role of endothelial IRE1 signaling in TBI using EC-specific IRE1 conditional knockout mice subjected to cortical ablation. Loss of IRE1 in ECs exacerbated blood-brain barrier (BBB) disruption, enhanced immune cell infiltration, amplified neuroinflammation, and expanded neuronal damage, ultimately leading to worsened neurological outcomes. RNA-sequencing revealed enrichment of interferon-related programs and identified Cxcl10 as an endothelial chemokine linked to the exacerbated leukocyte recruitment in endothelial IRE1 deficiency. Treatment with the chemical chaperone tauroursodeoxycholic acid (TUDCA) suppressed Cxcl10 expression both in vitro and in vivo, and significantly improved motor function following TBI. These findings reveal a critical role for endothelial IRE1 signaling in maintaining BBB integrity and restraining inflammation during the acute phase of TBI. Modulation of ER stress in brain ECs may represent a promising and accessible therapeutic strategy for reducing secondary injury after TBI.
    DOI:  https://doi.org/10.1038/s41419-026-08461-2
  5. Molecules. 2026 Feb 05. pii: 559. [Epub ahead of print]31(3):
    Targeting the UPR with Small Molecules: Emerging Strategies for Immune Regulation.
    Junyi Duan, Daoyuan Huang, Yick W Fong.
      The unfolded protein response (UPR) is a highly conserved adaptive mechanism that restores endoplasmic reticulum (ER) homeostasis under stress. Beyond its canonical roles in proteostasis, the UPR has emerged as a central regulator of immune responses across diverse contexts, including infection, inflammation, cancer, and autoimmunity. IRE1α, PERK, and ATF6 are three principal UPR sensors that coordinate complex signaling networks to regulate antigen presentation, cytokine production, and immune cell differentiation. This review highlights the molecular mechanisms by which small molecules target the UPR to modulate immune responses. In addition, we highlight stress granules (SGs) and the prevalence of protein-protein interactions mediated by intrinsically low-complexity domains (LCDs) in the UPR as potential new avenues for immune modulation. Finally, we discuss future directions for leveraging UPR modulation in immunotherapy, infectious disease, and chronic inflammatory disorders.
    Keywords:  ER; LCD; SG; UPR; immunity; small molecules
    DOI:  https://doi.org/10.3390/molecules31030559
  6. Mol Cancer Ther. 2026 Feb 11.
    Unfolded Protein Response as a Therapeutic Target: 4-(Heptyloxy)phenol Induces Programmed Cell Death in Ewing Sarcoma.
    Nenggang Zhang, Mary Perez, Gaye N Jenkins, Terzah M Horton, Scott R Gilbertson, Debananda Pati.
      Ewing sarcoma (ES) is a rare and aggressive pediatric malignancy with limited therapeutic options, particularly for relapsed or refractory cases, highlighting the urgent need for innovative treatment strategies. In this study, we identify endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) as critical therapeutic vulnerabilities in ES and introduce 4-(heptyloxy)phenol (AC-45594) as a novel small-molecule agent that exploits these stress pathways. AC-45594 selectively inhibited the growth of ES cells among thirteen cancer and six non-cancerous cell lines, demonstrating marked tumor specificity. Structure-activity relationship studies revealed that both the phenolic hydroxyl group and an optimal alkoxy chain length (7-9 carbon atoms) are essential for its activity. Mechanistically, AC-45594 induces ERS, activates UPR, and drives a shift from adaptive to terminal stress signaling, culminating in apoptosis of ES cells. Proteomic and gene expression analyses further supported selective activation of proapoptotic UPR signaling. These findings establish ERS and UPR as actionable targets in ES and position AC-45594 as a first-in-class compound capable of selectively inducing stress-driven cell death. This work lays the foundation for a new class of therapeutics targeting maladaptive stress responses in pediatric sarcomas and potentially other hard-to-treat cancers.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-0798
  7. Cell Rep. 2026 Feb 11. pii: S2211-1247(26)00054-9. [Epub ahead of print]45(2): 116976
    Triglycerides induce endoplasmic reticulum lipid bilayer stress to activate PERK and enhance antifungal immunity.
    Han Wu, Qing Shui, Xiaoxi Luan, Kexin Wang, Wei Zhao, Xiaopeng Qi, Bingyu Liu, Wanwei Sun, Chengjiang Gao.
      Invasive fungal infections remain a major clinical challenge due to limited antifungal drugs, drug toxicity, and resistance. Fungal infections trigger endoplasmic reticulum (ER) stress. However, the mechanism through which this stress response affects antifungal immunity remains unclear. Here, we showed that de novo triglyceride synthesis promotes antifungal innate immune signaling and proinflammatory gene expression in macrophages. Upon fungal stimulation, triglycerides induce ER lipid bilayer stress and activate the protein kinase R (PKR)-like ER kinase (PERK) branch of the unfolded protein response pathway. Furthermore, activated PERK mediates autophagic degradation of Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) to amplify spleen tyrosine kinase-associated antifungal signaling. Mice with PERK deficiency in myeloid cells are more susceptible to the lethal sequelae of systemic infection with Candida albicans. Notably, administration of the PERK agonist CCT020312 improved host outcomes in disseminated fungal infections. Overall, our study identified a critical function of PERK in positively regulating antifungal immune responses and offers a potential therapeutic strategy for controlling C. albicans infections.
    Keywords:  CP: immunology; CP: metabolism; PERK; antifungal immunity; drug target; lipid bilayer stress; triglycerides
    DOI:  https://doi.org/10.1016/j.celrep.2026.116976
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