bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–05–17
six papers selected by
Susan Logue, University of Manitoba
  1. Tunicamycin-induced ER stress promotes inflammation in SH-SY5Y cells through ROS-NF-κB-SIRT1 pathway.
  2. Targeting endoplasmic reticulum stress for neuroprotection in ischemia-reperfusion injury: mechanisms and therapeutic approaches.
  3. Exercise-induced modulation of the unfolded protein response: a therapeutic avenue for muscle wasting disorders.
  4. Loss of macroautophagy results in abnormality of the endoplasmic reticulum in insulin-secreting MIN6 cells.
  5. The IRE1 α -XBP1s-NF κ B axis controls cell survival and epithelial differentiation under osmotic stress through arachidonic acid metabolism activation.
  6. Endoplasmic Reticulum-Targeting NIR Cyanine ER800 Nanoparticles Promote Pyroptosis in Triple-Negative Breast Cancer.
  1. Mol Biol Rep. 2026 May 11. pii: 740. [Epub ahead of print]53(1):
    Tunicamycin-induced ER stress promotes inflammation in SH-SY5Y cells through ROS-NF-κB-SIRT1 pathway.
    Sreelekshmi G Jayan, A Jayakumaran Nair, Boban P T, Saja K.
       BACKGROUND: The accumulation of unfolded and misfolded proteins within the endoplasmic reticulum (ER) causes ER stress, leading to various physiological and pathological conditions. The cell activates unfolded protein response (UPR), an adaptive mechanism, to maintain the ER proteostasis. Neuronal ER stress can contribute to various neurodegenerative diseases. This study aims to investigate the effect of tunicamycin-induced ER stress on neuronal inflammation and the molecular mechanism involved.
    METHODS AND RESULTS: To study the ER stress-associated neuronal inflammation in vitro, we used tunicamycin-induced SH-SY5Y cell lines as the model system. PCR, ELISA, and immunoblot analysis were used to study mRNA and protein expressions. Reactive oxygen species (ROS) production was determined by flow cytometry, and cell viability was determined by MTT assay. Tunicamycin upregulated the mRNA expression of ER stress markers like PERK, ATF4, CHOP, IRE1, XBP1, ATF6 and BiP/GRP78. ER stress induction upregulated the secretion and expression of TNF-α as evidenced by ELISA, PCR and immunoblot analysis. The protein expression of iNOS, COX-2 and total ROS and mitochondrial ROS production were upregulated by tunicamycin in SH-SY5Y cells. Immunoblot analysis suggested that tunicamycin increased the acetylation of NF-κB p65 and downregulates the production of class III histone deacetylase SIRT1 in SH-SY5Y cells. Experiment using resveratrol confirmed the role of SIRT1 in the acetylation of NF-κB p65.
    CONCLUSION: Our results suggest that tunicamycin-induced ER stress upregulated neuronal inflammation through ROS-NF-κB- SIRT1 pathway, and targeting this pathway may provide greater therapeutic potential for managing neuronal inflammation associated with neurodegenerative diseases.
    Keywords:  ER stress; Neuronal inflammation; ROS; SIRT1; Tunicamycin; UPR
    DOI:  https://doi.org/10.1007/s11033-026-11894-9
  2. Mol Biol Rep. 2026 May 11. pii: 734. [Epub ahead of print]53(1):
    Targeting endoplasmic reticulum stress for neuroprotection in ischemia-reperfusion injury: mechanisms and therapeutic approaches.
    Nazrana Payal, Rishabh Charan Choudhary, Aditi Sharma, Lalit Sharma.
      The pathological condition known as ischemia reperfusion injury (IRI) is characterized by an initial restriction in the amount of blood supply followed by reperfusion which paradoxically aggravates irreversible neuronal damage and cell death. In Central Nervous System, IRI disrupts cytoskeletal integrity, causes dysruption in intracellular calcium homeostasis, and worsens mitochondrial function. Accruing evidence identifies endoplasmic reticulum (ER) stress and dysregulation of the unfolded protein response (UPR) as key contributors to ischemia-induced neurodegeneration. While transient ER stress activates adaptive signaling that supports cell survival, sustained or severe ER stress shifts UPR signaling toward pro-apoptotic pathways involving CHOP induction, calcium overload, mitochondrial dysfunction, and caspase activation. This review critically examines recent advances linking ER stress to neuronal injury following cerebral ischemia and reperfusion, with a particular emphasis on ER-mitochondrial crosstalk and apoptotic signaling. Importantly, we summarize and evaluate emerging therapeutic strategies targeting ER stress pathways including chemical chaperones, UPR modulators, calcium homeostasis regulators, and metabolic interventions-and discuss their neuroprotective potential and translational limitations. By integrating mechanistic insights with therapeutic perspectives, this review highlights ER stress as a promising but complex target for neuroprotection after ischemic injury.
    Keywords:  Endoplasmic Reticulum Stress; Ischemia-Reperfusion Injury; Mitochondrial Dysfunction; Neuroprotection; Therapeutic Targets; Unfolded Protein Response
    DOI:  https://doi.org/10.1007/s11033-026-11915-7
  3. J Physiol Biochem. 2026 May 11. pii: 50. [Epub ahead of print]82(1):
    Exercise-induced modulation of the unfolded protein response: a therapeutic avenue for muscle wasting disorders.
    Ao Ke, Zhuo Jinyuan, Lijuan Xiang, Zhanguo Su.
      Muscle wasting, prevalent in various pathological conditions including cancer, cardiac dysfunction, and neurodegeneration, is typified by sustained protein depletion in muscle and a compromised ability of the tissue to repair and regenerate effectively. Triggered by disruptions in protein folding in the endoplasmic reticulum (ER), the unfolded protein response (UPR) represents a key regulatory system that sustains intracellular proteostasis under conditions of stress. While the UPR is crucial for cellular survival, prolonged activation or dysfunction of the pathway can contribute to muscle atrophy and the progression of muscle wasting diseases. Recent evidence suggests that exercise, through its impact on cellular stress responses, can modulate the UPR in muscle cells, promoting a protective response that enhances protein folding capacity, reduces ER stress, and stimulates muscle regeneration. This review explores how exercise influences the UPR in muscle cells, focusing on the activation of key UPR sensors, including IRE1, PERK, and ATF6, and their downstream effects on protein quality control, autophagy, and muscle fiber maintenance. We also examine the role of exercise in promoting adaptive responses in muscle cells, including increased mitochondrial function, autophagy, and the activation of stress resistance pathways, all of which can counteract muscle wasting. The review also emphasizes exercise as an effective strategy to influence ER stress pathways and attenuate muscle atrophy associated with pathological conditions, offering critical insights into the molecular benefits of physical activity for muscle preservation.
    Keywords:  Autophagy; Endoplasmic reticulum stress; Exercise; Muscle wasting; Unfolded protein response
    DOI:  https://doi.org/10.1007/s13105-026-01190-2
  4. Cell Struct Funct. 2026 May 09.
    Loss of macroautophagy results in abnormality of the endoplasmic reticulum in insulin-secreting MIN6 cells.
    Asako Kishimoto, Shunsuke Saito, Byungseok Jin, Shigeomi Shimizu, Satoko Arakawa, Kazutoshi Mori.
      Macroautophagy is a highly conserved system that degrades various materials inside the cell ranging from proteins to organelles. Atg5 is a protein essential for the formation of autophagosomes, which sequester materials by double membrane and degrade them after fusion with lysosomes. MIN6 cells derived from mouse pancreatic β cells retain the ability to secrete insulin in response to a change in glucose concentration from low to high. We knocked out the Atg5 gene in MIN6 cells and identified an abnormality in the endoplasmic reticulum (ER) under normal culture conditions using electron microscopy. The ER was slightly enlarged and the ER membrane was ruptured at some places adjacent to inclusion body-like structures. Numerous granule-like structures were accumulated in the lumen of the ER, some of which appeared to have leaked into the cytoplasm. These abnormalities caused ER stress, resulting in activation of all three pathways (IRE1, PERK, and ATF6) of the unfolded protein response but no induction of apoptosis. We also observed the activation of alternative autophagy/Golgi membrane-associated degradation in Atg5-KO MIN6 cells, but this was insufficient for the removal of a majority of these granule-like structures from the ER. Thus, macroautophagy but not activation of the unfolded protein response or Golgi membrane-associated degradation is essential for the homeostasis of the ER in MIN6 cells.Key words: autophagy, endoplasmic reticulum, unfolded protein response, proinsulin, Golgi membrane-associated degradation.
    Keywords:  Golgi membrane-associated degradation; autophagy; endoplasmic reticulum; proinsulin; unfolded protein response
    DOI:  https://doi.org/10.1247/csf.26016
  5. Cell Stress. 2026 ;10 32-48
    The IRE1 α -XBP1s-NF κ B axis controls cell survival and epithelial differentiation under osmotic stress through arachidonic acid metabolism activation.
    Leandro Gastón Parra, Cecilia Irene Casali, Dylan Ezequiel Sendyk, Ailén Florencia Salafia, Sabrina Andrea Flor, Silvia Edith Lucangioli, María Del Carmen Fernández Tome.
      Arachidonic acid (AA) metabolism plays a critical role in renal cell osmoadaptation. We recently demonstrated that hypertonicity induces the expression and activation of cytosolic phospholipase A 2 (cPLA 2 ). On one hand, AA released by cPLA 2 enhances triacylglyceride (TG) synthesis and accumulation. On the other hand, AA is converted into prostaglandins (PG) through cyclooxygenase 2 (COX2) activity. Both processes are required for renal cell survival under osmotic stress. However, the mechanisms by which hypertonicity induces cPLA 2 expression remain poorly understood. Given that we previously shown that hypertonicity regulates TG synthesis through the IRE1 α -XBP1s branch of the unfolded protein response (UPR), here we examined whether XBP1s regulates the cPLA 2 -AA-COX2 axis in renal cells subjected to osmotic stress. We found that XBP1s modulates hypertonicity-induced expression of cPLA 2 and COX2 by increasing NF κ B transcriptional activity. Inhibition of IRE1 α impaired normal COX2 degradation and disrupted AA metabolism, leading to a decrease in cell viability and preventing hypertonicity-induced epithelial differentiation. Prostaglandin E2 (PGE2) contributed to cell polarization facilitating adherens junction (AJ) assembly. Together, these findings highlight a central role for the IRE α -XBP1s-NF κ B signaling axis in coordinating cell stress responses and epithelial differentiation through AA metabolism activation.
    Keywords:  ER stress; arachidonic acid; cell differentiation; cyclooxygenase 2; osmotic stress; phospholipase A2; unfolded protein response
    DOI:  https://doi.org/10.15698/cst2026.04.317
  6. ACS Appl Mater Interfaces. 2026 May 15.
    Endoplasmic Reticulum-Targeting NIR Cyanine ER800 Nanoparticles Promote Pyroptosis in Triple-Negative Breast Cancer.
    Jiawang Yang, Jijun Jiang, Yuanzhi Yang, Zhilin Shen, Zhixuan Lin, Xianpin Gao, Wei Wu, Zongjian Ye, Jie Gao, Ning Gao.
      Pyroptosis, an inflammatory form of cell death, has recently attracted increasing attention in anticancer therapy. Endoplasmic reticulum (ER)-targeted pyroptosis has emerged as a highly promising strategy in theranostics, integrating tumor imaging and therapeutic interventions. Research on the use of ER-targeted theranostic agents for triggering pyroptosis is lacking. This study aims to develop an ER-targeting theranostic agent that enables the integration of tumor imaging and cancer-targeted therapeutics. The ER-targeting NIR fluorescent cyanine ER800 was synthesized, and ER800-FA-NPs were constructed. Flow cytometry, immunofluorescence, and Western blotting were employed to assess the ER targeting effect and pyroptosis in triple-negative breast cancer (TNBC) cells in vitro. A TNBC cell xenograft model was used to investigate the antitumor efficacy. ER800-FA-NPs preferentially accumulate in the ER of TNBC cells, subsequently promoting ER stress via the generation of ROS. High ER stress triggers the activation of the GRP78-mediated PERK-eIF2α-ATF4-CHOP, ATF6, and IRE1-XBP1 signaling pathways, leading to LDH, IL-1β, and IL-18 release and cleavage of caspase-3/GSDME and ultimately promoting pyroptosis. In vivo experiments revealed that ER800-FA-NPs exhibited excellent tumor-targeting ability and antitumor efficacy against TNBC through caspase-3/GSDME pathway-mediated pyroptosis. Our research findings indicate that ER800-FA-NPs may serve as theranostic agents in tumor imaging-guided therapy, further supporting the use of ER-targeted pyroptosis for the treatment of TNBC.
    Keywords:  ER800; NIR cyanine; endoplasmic reticulum targeting; nanoparticles; pyroptosis; triple-negative breast cancer
    DOI:  https://doi.org/10.1021/acsami.6c03104
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒17 at 20:50.