bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–01–04
eight papers selected by
Susan Logue, University of Manitoba
  1. ER stress sensors at the ER-mitochondrial interface, controlling mitochondrial health in neurodegenerative diseases.
  2. Advances in study of endoplasmic reticulum stress in ophthalmic diseases: an overview.
  3. The role of bHLH-PAS transcription factors in endoplasmic reticulum stress.
  4. Endoplasmic reticulum stress in non-small cell lung cancer: a review of therapeutic agents, mechanistic insights, and implications for therapy.
  5. bZIP factors of the Unfolded Protein Response interact with PIF4 to promote thermomorphogenesis.
  6. HOXA2 exerts anti-renal fibrosis effects through reducing endoplasmic reticulum stress via the upregulation of SIRT1.
  7. Exercise impact on IRE1α signaling: Novel insights into Alzheimer's disease prevention and treatment.
  8. HER3 enhances ATF4 induction and survival in breast cancer cells during endoplasmic reticulum stress.
  1. Front Neurosci. 2025 ;19 1665272
    ER stress sensors at the ER-mitochondrial interface, controlling mitochondrial health in neurodegenerative diseases.
    Chaitanya Kunja, Vaishali Kumar, Pradeep Kodam, Chamundeshwari Devi Gopu, Shuvadeep Maity.
      The endoplasmic reticulum (ER) and mitochondria are essential organelles that interact closely at specialized sites known as ER-mitochondria-associated membranes (MAMs). MAM is enriched with proteins from both the ER and mitochondria. ER stress sensors-inositol-requiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) - are traditionally recognized for their roles in the unfolded protein response (UPR), which mitigates proteotoxic stress. However, recent studies reveal their non-canonical functions at MAMs, where they regulate calcium signaling, mitochondrial dynamics, and apoptosis through interactions with MAM-resident proteins. Disruption of these pathways is implicated in various diseases, particularly neurodegenerative disorders. This review highlights the emerging roles of IRE1 and PERK in preserving mitochondrial function and their relevance to neurodegeneration. It also examines pharmacological strategies targeting these proteins, which influence both UPR signaling and ER-mitochondrial communication, offering a comprehensive perspective on their roles in health and disease.
    Keywords:  ER stress sensors; ER-mitochondrial interactions; IRE1; UPR signaling; mitochondrial health; neurodegenerative diseases; pERK
    DOI:  https://doi.org/10.3389/fnins.2025.1665272
  2. Biochem Biophys Res Commun. 2025 Dec 22. pii: S0006-291X(25)01898-4. [Epub ahead of print]797 153182
    Advances in study of endoplasmic reticulum stress in ophthalmic diseases: an overview.
    Miao Zhang, Hongsheng Bi, Dadong Guo.
      The endoplasmic reticulum (ER) is a vital intracellular organelle in protein synthesis, folding, and modification. When cells experience excessive protein synthesis, glucose metabolism disorders, or calcium imbalance, the ER can become damaged or overburdened, triggering ER stress. Dysregulated ER stress can lead to various pathophysiological processes, including apoptosis, inflammation, protein aggregation, and lipid metabolism abnormalities. These processes are closely associated with the onset and progression of numerous diseases. Notably, many ophthalmic conditions, such as age-related macular degeneration, glaucoma, and diabetic retinopathy, are intricately linked to ER stress. This review provides a concise overview of the role of ER stress in the development and progression of ophthalmic diseases. It also explores the potential of targeting ER stress as a therapeutic approach for these conditions. By modulating ER stress and its associated pathways, new therapeutic strategies may be developed to improve patient outcomes. Future research should aim to elucidate the specific molecular mechanisms linking ER stress to ophthalmic diseases and to validate the efficacy and safety of interventions targeting ER stress, offering new perspectives and methods for the prevention and treatment of ophthalmic diseases.
    Keywords:  Age-related macular degeneration; Cataracts; Endoplasmic reticulum stress; Glaucoma
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153182
  3. Front Mol Biosci. 2025 ;12 1730502
    The role of bHLH-PAS transcription factors in endoplasmic reticulum stress.
    Izabela Krauze, Małgorzata Krzystek-Korpacka, Kamila Maciejewska, Beata Greb-Markiewicz.
      The bHLH-PAS protein family consists of transcription factors that are involved in the regulation of key physiological processes such as the response to hypoxia, circadian rhythms, the detoxification of xenobiotics, and metabolic homeostasis. These proteins act as environmental sensors, integrating diverse signals into transcriptional responses. In recent years, increasing attention has been paid to their role in regulating endoplasmic reticulum stress (ER stress), which is an adaptive cellular response to disturbances in protein-folding. Prolonged or severe ER stress can activate the unfolded protein response (UPR) and apoptotic pathways, contributing to the development of numerous disorders, including neurodegenerative, cancerous, and inflammatory diseases. This review focuses on the functions of bHLH-PAS proteins, such as AHR, HIF, SIM, NPAS1-4, and CLOCK, with particular emphasis on their potential role in modulating ER stress. Molecular mechanisms through which these proteins regulate responses to hypoxia and other cellular stressors are also discussed, with a focus on their importance in maintaining homeostasis and their potential as therapeutic targets.
    Keywords:  bHLH-PAS domain proteins; cellularstress; endoplasmic reticulum stress; therapeutic targets; transcriptional factors
    DOI:  https://doi.org/10.3389/fmolb.2025.1730502
  4. Front Cell Dev Biol. 2025 ;13 1693023
    Endoplasmic reticulum stress in non-small cell lung cancer: a review of therapeutic agents, mechanistic insights, and implications for therapy.
    Qiong Luo, Xinxin Gao, Peng Meng, Xiao Qi, Wen Wang, Shan Li, Linlin Duan.
      Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with therapy resistance significantly hindering treatment efficacy. This review explores the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in NSCLC progression and resistance mechanisms. Under stress conditions such as hypoxia, nutrient deprivation, or therapeutic insult, the UPR balances adaptive survival signaling and apoptotic pathways. Key UPR sensors-PERK, IRE1α, and ATF6-are dysregulated in NSCLC, enabling tumor cells to evade death despite microenvironmental or treatment-induced stress. Preclinical studies highlight therapeutic strategies targeting ER stress through reactive oxygen species (ROS) induction, calcium homeostasis disruption, and proteasome inhibition, which shift the UPR toward pro-apoptotic outcomes. Agents such as proteasome inhibitors, natural compounds, and repurposed drugs demonstrate the potential to overcome resistance by enhancing chemosensitivity, reversing chemoresistance, and improving radiosensitivity. Combination therapies synergize ER stress inducers with conventional treatments, leveraging immunogenic cell death (ICD) to augment anti-tumor immunity. However, challenges persist due to the UPR's context-dependent outputs and the gap between preclinical models and clinical applicability. Future directions include optimizing combination regimens, identifying predictive biomarkers, and advancing personalized approaches. Translating these insights into clinical trials is critical to validate ER stress modulation as a viable strategy for improving NSCLC outcomes, offering a promising avenue to address unmet needs in this aggressive malignancy.
    Keywords:  endoplasmic reticulum stress; immunogenic cell death; non-small cell lung cancer; therapy resistance; unfolded protein response
    DOI:  https://doi.org/10.3389/fcell.2025.1693023
  5. Nat Commun. 2025 Dec 30.
    bZIP factors of the Unfolded Protein Response interact with PIF4 to promote thermomorphogenesis.
    Dan Zhang, Haiying Xu, Nam-Hai Chua.
      When Arabidopsis plants are exposed to warm temperatures (e.g., 29 °C), they undergo adaptive growth known as thermomorphogenesis. This process is primarily regulated by the phytochrome B (phyB)-PHYTOCHROME-INTERACTING FACTOR 4 (PIF4) module; however, the potential involvement of additional signaling pathways remains underexplored. Here, we show that warmth triggers endoplasmic reticulum (ER) stress, activating both arms of the Unfolded Protein Response (UPR). Three UPR-associated bZIP transcription factors, bZIP17, bZIP28 and bZIP60, promote hypocotyl growth under warmth in a PIF4-dependent manner. Active bZIP factors form complexes with PIF4 in the nucleus, where they bind to promoter regions of PIF4 and other growth-related genes to enhance their expression. In parallel, bZIPs overexpression counteract the inhibitory effect of phyB on PIF4 stability, thereby reinforcing thermomorphogenic growth. Together, our findings define a regulatory axis that links ER stress, the UPR and thermomorphogenesis, clarifying how plants coordinate physiological and environmental cues to adapt to warming conditions.
    DOI:  https://doi.org/10.1038/s41467-025-67909-9
  6. Commun Biol. 2025 Dec 30.
    HOXA2 exerts anti-renal fibrosis effects through reducing endoplasmic reticulum stress via the upregulation of SIRT1.
    Xin Li, Tian-Kui Ma, Xiao-Xu Deng, Sang Hai, Fang Ma, Yun Zou, Qi Yang, Hui Lyu, Yu-Xi Li, Hong Ding.
      Relieving renal fibrosis are promising therapeutic strategies for chronic kidney disease (CKD). Here we showed that decreased homeobox A2 (HOXA2) expression with excessive ER stress activation were observed in the renal tissues of UUO mice established on male C57BL/6 mice and TGF-β1-induced human proximal tubular epithelial cells (HK-2 cells). After transfected HOXA2 overexpression plasmids into HK-2 cells and administered adeno-associated virus (AAV) containing HOXA2 to UUO mice, the expression of ER stress markers such as ATF6, GRP78 and CHOP decreased, renal dysfunction and fibrosis were significantly attenuated. Mechanistically, HOXA2 binds to the SIRT1 promoter, enhancing SIRT1 transcription and deacetylase activity, which led to ATF6 deacetylation and downregulation. The protective effect of HOXA2 was confirmed against the ER stress agonist thapsigargin. Moreover, DNMT1-mediated promoter methylation was identified as a potential mechanism for HOXA2 suppression in fibrosis. Targeting HOXA2 maybe an innovative therapeutic strategy for fibrosis treatment in CKD.
    DOI:  https://doi.org/10.1038/s42003-025-09453-2
  7. Biochem Biophys Res Commun. 2025 Dec 18. pii: S0006-291X(25)01872-8. [Epub ahead of print]797 153156
    Exercise impact on IRE1α signaling: Novel insights into Alzheimer's disease prevention and treatment.
    Tu Haixia, Xu Bo.
      Endoplasmic reticulum stress (ERS) and its downstream signaling play a central role in neuroinflammation in Alzheimer's disease (AD). Among them, IRE1α, as a key sensor of ER stress, is a pivotal molecule connecting stress to inflammation. Its aberrant activation drives neuroinflammation, which in turn exacerbates Aβ deposition, Tau pathology, and cognitive decline. Therefore, targeting the IRE1α signaling pathway has become a potential strategy for AD intervention. Recent studies suggest that exercise can alleviate ER stress and directly or indirectly inhibit the excessive activation of IRE1α, thereby reducing its downstream inflammatory signals. This review aims to systematically elucidate the pathogenic mechanism of the IRE1α inflammatory signaling pathway in AD. It also focuses on exploring the evidence of the neuroprotective effect of exercise through regulating this pathway, providing new theoretical basis and direction for exercise-based prevention and treatment of AD.
    Keywords:  Alzheimer's disease; ERS; Exercise; IRE1α
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153156
  8. Biochem Biophys Res Commun. 2025 Dec 26. pii: S0006-291X(25)01931-X. [Epub ahead of print]797 153215
    HER3 enhances ATF4 induction and survival in breast cancer cells during endoplasmic reticulum stress.
    Miku Otsuka, Yuka Okamoto, Akiko Hasebe, Hitomi Shirahama, Akihiro Tomida.
      Oncogenic signaling and stress response pathways interact to drive tumorigenesis and therapy resistance. However, little is known about such interactions for HER3, a member of the HER/ErbB receptor family that is aberrantly expressed in many tumors, including breast cancer. Here, we show that HER3 cooperates with HER2 to enhance induction of ATF4, a central transcription factor of the integrated stress response and the unfolded protein response, during endoplasmic reticulum (ER) stress. ATF4 induction was enhanced by ligand-activated HER3 and conversely reduced by genetic knockdown or pharmacological inhibition of HER2/HER3-mediated signaling in both HER2-overexpressing SKBR3 and non-overexpressing MCF7 breast cancer cells. HER3 knockdown in SKBR3 cells also increased cell death during ER stress. Notably, depletion of HER3, likely occurring through ER stress-associated downregulation mechanisms, was accompanied by attenuation of ATF4 induction during sustained stress. These findings suggest that the HER3-ATF4 axis functions as a dynamically regulated mechanism for tuning the cellular stress response.
    Keywords:  ATF4; Breast cancer; HER2; HER3; Integrated stress response
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153215
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒05 at 22:58.