bims-unfpre 2026-05-31 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–05–31
twelve papers selected by
Susan Logue, University of Manitoba

Flavivirus-Induced ER Stress and Unfolded Protein Response: A Central Hub Linking Lipid Droplet Remodeling and Viral Replication.
Nuclear Receptor Liver Receptor Homolog-1 drives Intestinal Stem Cell regeneration and UPR/ER stress response after gut injury.
CHOP promotes the transition to chronic integrated stress response signaling with suppression of hepatocyte identity.
Role of the IRE1α-XBP1 Axis in IgE-Dependent Activation of Mast Cells.
Redox control at the ER-mitochondria interface in kidney transplantation: MAM-centered stress signaling and translational organoid platforms.
DDIT3 Promotes Starvation-Induced Autophagy via ER Stress in Vero Cells.
The yin and yang interplay between HDAC6 and KDM1 regulates the lysosomal degradation of mutp53 in colon cancer cells undergoing TG-induced ER stress.
FOXA1-mediated CEPT1 deficiency in airway epithelium drives asthma via an ER stress-mitochondrial dysfunction axis.
Lifestyle intervention is associated with attenuation of ER stress/inflammation and enhancement of naive immune cell identity in older adults with metabolic disease.
Identification and analysis of endoplasmic reticulum stress-related genes in neuroblastoma and construction of a prognostic gene signature.
Endoplasmic Reticulum-Targeted Biomimetic Nanoparticles Potentiate the Immunotherapy of Triple-Negative Breast Cancer by Improving Immunogenicity and Eliminating Immune Resistance.
Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.

Viruses. 2026 Apr 23. pii: 493. [Epub ahead of print]18(5):

Flavivirus-Induced ER Stress and Unfolded Protein Response: A Central Hub Linking Lipid Droplet Remodeling and Viral Replication.

Imaan Muhammad, Kaci Craft, Shaokai Pei, Ruth Cruz-Cosme, Qiyi Tang.

  Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) represent fundamental cellular adaptive mechanisms that maintain protein homeostasis and metabolic balance. Many RNA viruses, particularly flaviviruses such as dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), yellow fever virus (YFV), and Japanese encephalitis virus (JEV), extensively remodel the ER to establish replication compartments and assemble progeny virions. This massive reorganization disrupts ER homeostasis, leading to UPR activation. Emerging evidence reveals that flaviviruses not only trigger but also manipulate the three UPR branches-PERK, IRE1, and ATF6-to optimize viral translation, replication, and egress. In parallel, flavivirus infection profoundly alters host lipid metabolism and promotes dynamic changes in lipid droplets (LDs), key organelles that mediate lipid storage and serve as scaffolds for viral replication and assembly. The UPR intimately connects to LD biogenesis through transcriptional and translational programs mediated by XBP1, ATF4, and ATF6, thereby coupling ER stress responses to lipid remodeling and energy homeostasis. This intricate crosstalk between UPR and LDs creates a metabolic and structural niche favorable for viral replication but detrimental to host cell integrity. This review provides a comprehensive analysis of the molecular mechanisms by which flaviviruses exploit ER stress and the UPR to reprogram lipid metabolism and LD dynamics. We highlight the dual role of UPR signaling in promoting adaptive lipid synthesis and initiating cell death under prolonged stress, discuss recent insights into ER-LD interactions during flavivirus infection, and explore therapeutic opportunities targeting UPR-lipid metabolic pathways as broad-spectrum antiviral strategies. Understanding this interconnected network will advance our knowledge of viral pathogenesis and identify new avenues for host-directed antiviral intervention.

Keywords:  ER stress; Zika virus; activating transcription factor 6 (ATF6); flavivirus; inositol-requiring enzyme 1 (IRE1); lipid droplet; protein kinase RNA-like ER kinase (PERK); unfolded protein response; viral replication

DOI:  https://doi.org/10.3390/v18050493
bioRxiv. 2026 May 17. pii: 2026.05.15.725547. [Epub ahead of print]

Nuclear Receptor Liver Receptor Homolog-1 drives Intestinal Stem Cell regeneration and UPR/ER stress response after gut injury.

Hsi-Ju Chen, Kristina N Braverman, Bohan Yu, James R Bayrer.

Stem cell renewal and crypt survival are tightly controlled processes critical for gut repair. Defining key regulators of intestinal healing is critical for the development of new epithelial-targeted therapies. We previously showed that the nuclear receptor LRH-1 (NR5A2) maintains intestinal epithelial health and protects against inflammatory damage. Here, using lineage tracing and selective LRH-1 knockout in the Atoh1 + secretory lineage we show LRH-1 is vital for intestinal stem cell (ISC) regeneration in complementary in vivo and ex vivo injury-recovery models. Transcriptomic profiling and pathway analysis reveal downregulation of ER stress and unfolded protein response (UPR) programs. Using a new in vivo model to ascertain how LRH-1 directly impacts intestinal cell responses, we identify key ER stress response genes Ire1α and Xbp1 as potential LRH-1 targets. Together our results uncover a novel mechanism whereby LRH-1 sustains the IRE1α-XBP1 arm of the UPR to support injury-induced dedifferentiation and ISC regeneration. Our findings highlight LRH-1 as a promising therapeutic target for restoring epithelial integrity in inflammatory intestinal disorders.

DOI: https://doi.org/10.64898/2026.05.15.725547
bioRxiv. 2026 May 15. pii: 2026.05.13.724984. [Epub ahead of print]

CHOP promotes the transition to chronic integrated stress response signaling with suppression of hepatocyte identity.

Theo F Velarde, Kaihua Liu, Zewei Zhang, Reed C Adajar, Chaoxian Zhao, Huojun Cao, D Thomas Rutkowski.

The transcription factor CHOP promotes cell death during ER stress, but it is strongly induced even by moderate stresses that do not result in appreciable cell death. Its role during less severe stresses-especially in intact tissues in vivo -is poorly understood. Here, we both deleted and restored CHOP specifically in hepatocytes and challenged animals with ER stress in vivo . We found that CHOP influenced stress-dependent hepatocyte gene expression through two previously unappreciated mechanisms. It directly suppressed the expression of transcriptional master regulators of hepatocyte identity and metabolism. And more broadly, it exacerbated ER stress through the promotion of protein synthesis, which led to persistent activation of the integrated stress response (ISR) despite dephosphorylation of eIF2α. This shift to second-phase ISR signaling was phenocopied by deletion of the protective UPR sensor ATF6α, suggesting that it reflects a transition from an acute stress response to a chronic one. Our findings show that CHOP augments the capacity of the ISR and UPR to continue to mount a protective response even after eIF2α phosphorylation has been suppressed. In vivo , where ISR signaling intersects with hepatocyte gene regulatory networks, this transition favors lipid dysregulation, highlighting a pathway through which CHOP impacts tissue function independent of cell death.

DOI: https://doi.org/10.64898/2026.05.13.724984
Int J Mol Sci. 2026 May 18. pii: 4532. [Epub ahead of print]27(10):

Role of the IRE1α-XBP1 Axis in IgE-Dependent Activation of Mast Cells.

Hiroto Kouda, Kazuki Nagata, Riu Saito, Chiharu Nishiyama.

  The IRE1α-XBP1 axis is the most conserved of the three major unfolded protein response (UPR) branches triggered by the endoplasmic reticulum (ER) stress. Although the transcription factor XBP1 is involved in the development and function of several hematopoietic lineages, its role in the activation of mast cells (MCs), which are critical in allergic responses, remains largely unknown. We identified salicylaldehyde, which suppresses IRE1α nuclease activity that is essential for XBP1 production, as an inhibitor of MC activation in our previous screening; therefore, we herein investigated the effects of additional IRE1α inhibitors, 3-methyl-6-bromo-salichylaldehyde (MBSA) and KIRA6, targeting the nuclease domain and kinase domain, respectively, on MC activation. MBSA and KIRA6 suppressed IgE-dependent degranulation of bone marrow-derived MCs (BMMCs) but did not inhibit Ca2+ ionophore- or compound48/80-induced degranulation. Treatments with inhibitors of two other branches of UPR, the PERK and ATF6 pathways, did not affect the IgE-induced activation of BMMCs. The intraperitoneal administration of MBSA or KIRA6 significantly suppressed IgE-induced passive anaphylaxis in mice. Furthermore, to examine the effects of XBP1, siRNA-mediated knockdown was performed. The results obtained confirmed that Xbp1 siRNA introduction reduced the IgE-dependent degranulation of BMMCs in parallel with the knockdown level of Xbp1 mRNA. Therefore, the IRE1α-XBP1 axis plays a significant role in IgE-dependent and MC-mediated allergic responses and is considered to be a therapeutic target of allergic diseases.

Keywords:  IRE1α; IgE; XBP1; mast cell; siRNA; unfolded protein response

DOI:  https://doi.org/10.3390/ijms27104532
Redox Biol. 2026 May 26. pii: S2213-2317(26)00234-X. [Epub ahead of print]94 104236

Redox control at the ER-mitochondria interface in kidney transplantation: MAM-centered stress signaling and translational organoid platforms.

Baicheng Kuang, Lin Han, Sopheaktra Tan, Sokun Tan, Sopheap Bou, Yuanyuan Zhao, Yan Li, Jiasheng Yu, Nianqiao Gong.

  Kidney transplantation is inevitably accompanied by ischemia-reperfusion injury in which oxidative stress and endoplasmic reticulum (ER) stress act as tightly interconnected drivers of mitochondrial dysfunction, inflammation, and long-term graft failure. Excessive reactive oxygen species disrupt mitochondrial homeostasis, while unresolved ER stress activates maladaptive unfolded protein response signaling, together shaping tubular cell fate. Although these processes have been extensively studied, their spatial and functional integration remains incompletely understood. Growing evidence indicates that oxidative stress and ER stress converge at mitochondria-associated membranes (MAMs), where calcium signaling, redox regulation, and stress-adaptive networks are integrated. However, the dynamic and context-dependent nature of MAM remodeling remains poorly defined and difficult to investigate using conventional experimental systems. In this review, we propose a MAM-centered framework that integrates cellular stress responses, with a particular focus on ischemia-reperfusion in kidney transplantation. We further highlight therapeutic strategies targeting MAM-associated pathways, including mitochondria-directed antioxidants, ER oxidoreductases and structural and signaling proteins of MAM. In parallel, we summarize emerging kidney organoid platforms as human-relevant translational systems for modeling MAM dynamics under controlled conditions. By integrating mechanistic insights with organoid-based investigations, this review bridges a critical gap between molecular understanding and translational application, and offers a conceptual framework for MAM-targeted strategies aimed at improving graft resilience and long-term transplant outcomes.

Keywords:  Endoplasmic reticulum stress; Kidney transplantation; Mitochondria-associated membranes; Mitochondrial dysfunction; Organoid; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2026.104236
Int J Mol Sci. 2026 May 12. pii: 4315. [Epub ahead of print]27(10):

DDIT3 Promotes Starvation-Induced Autophagy via ER Stress in Vero Cells.

Muzi Li, Renhou Jia, Rong Huang, Jiamin Wang, Zilin Qiao, Na Sun.

  Vero cells in high-density vaccine cultures often face nutrient starvation, especially in suspension-adapted Vero cells. Previous studies showed that serum starvation dramatically enhances autophagy and mitophagy in suspension-adapted Vero cells. Transcriptomic profiling also revealed significant upregulation of DDIT3, a marker of endoplasmic reticulum stress (ERS), in suspension-adapted Vero cells compared to adherent cells. To investigate the functional role of DDIT3, an Earle's Balanced Salt Solution (EBSS)-induced starvation model was established in adherent Vero cells, recapitulating key autophagy and ER stress responses observed under suspension conditions. The genetic silencing of DDIT3 by shRNA attenuated autophagy, as evidenced by a reduced LC3-II/LC3-I ratio and impaired autophagosome-lysosome activity. Notably, DDIT3 knockdown enhanced cell proliferation and increased the yield of H1N1 influenza virus under nutrient-deprived conditions. Collectively, these results suggest that DDIT3 may serve as a critical regulator linking ER stress to autophagy in Vero cells, and that the suppression of DDIT3 may represent a promising strategy for developing autophagy-resistant Vero cell lines suitable for high-density suspension culture in vaccine production.

Keywords:  DDIT3; Vero cells; autophagy; endoplasmic reticulum stress (Ers)

DOI:  https://doi.org/10.3390/ijms27104315
Biochim Biophys Acta Mol Cell Res. 2026 May 26. pii: S0167-4889(26)00062-5. [Epub ahead of print]1873(5): 120164

The yin and yang interplay between HDAC6 and KDM1 regulates the lysosomal degradation of mutp53 in colon cancer cells undergoing TG-induced ER stress.

Rossella Benedetti, Rosanna Paola Amato, Michele Di Crosta, Maria Saveria Gilardini Montani, Roberta Santarelli, Roberta Gonnella, Gabriella D'Orazi, Mara Cirone.

  Post-translational modifications (PTMs) play a key role in regulating protein/protein interactions and protein stability, thus influencing protein expression and function. HSPs and p53, including its wtp53 and mutp53 forms, make no exception to this rule, although the impact of PTMs on the regulation of these proteins has not yet been fully elucidated, particularly in the case of mutp53. These proteins, unlike wtp53, can behave as oncogenes, making their targeting an important step for successful anticancer therapy. We previously reported that mutp53 is degraded, preferentially via CMA, in colon cancer cells stressed by long-term TG treatment. Whether TG could induce PTMs and how they could contribute to mutp53 degradation has not yet been investigated and will be explored in this study. Acetylation of mutp53, as well as HSP90, has been reported to promote mutp53 degradation. However, we found that TG promoted deacetylation of mutp53 and HSP90, due to the sustained activity of HDAC6, a PTM that protected mutp53 from degradation. We then found that mutp53 was progressively demethylated by KDM1 at lysine K370 during TG treatment, which facilitated the interaction with HSC70 involved in mutp53 protein degradation via CMA. In conclusion, this study suggests that, in colon cancer cells subjected to stress by TG, mutp53 was degraded as a consequence of demethylation at lysine K370. Therefore, specific epigenetic drugs capable of reducing constitutive methylation and/or increasing acetylation could preemptively target mutp53 and improve the outcome of endoplasmic reticulum stress-inducing treatments in tumors harboring these proteins.

Keywords:  Colon cancer cells; ER stress; HSPs; Posttranslational modifications; mutp53

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120164
Cell Rep. 2026 May 22. pii: S2211-1247(26)00446-8. [Epub ahead of print]45(6): 117368

FOXA1-mediated CEPT1 deficiency in airway epithelium drives asthma via an ER stress-mitochondrial dysfunction axis.

Qile Chen, Yuyi Huang, Junjie Wen, Canyang Liang, Yuhuan Wen, Jing Wang, Suda Gu, Honglv Chen, Sijie Wu, Enli Zhang, Bowen Sun, Qingling Zhang, Jie Yan.

  Asthma is associated with disordered glycerophospholipid metabolism and decreased phosphatidylcholine (PC), but the molecular basis remains incompletely defined. Through integrative data mining, we identify CEPT1, a key enzyme in glycerophospholipid biosynthesis, to be significantly downregulated in the airway epithelium of asthma. CEPT1 deficiency causes PC/PE reduction and phospholipid imbalance, activates all three endoplasmic reticulum (ER) stress pathways, disturbs ER Ca2+ stores, and drives mitochondrial Ca2+ overload, which in turn triggers mitochondrial oxidative stress. Notably, administration of polyenylphosphatidylcholine (PPC) restores ER and mitochondrial homeostasis and reduces apoptosis, cytokine release, and mucus overproduction. FOXA1 is identified as a direct transcriptional activator of CEPT1. In vivo, CEPT1 overexpression alleviates airway inflammation and mucus hypersecretion. Collectively, our study elucidates an axis wherein FOXA1-mediated CEPT1 repression induces ER stress and mitochondrial dysfunction through disrupted calcium handling, driving mucin hypersecretion and airway inflammation-identifying CEPT1 restoration or PPC as potential mechanism-based interventions for asthma.

Keywords:  CEPT1; CP: cell biology; CP: immunology; ER stress; asthma; mitochondrial oxidative stress

DOI:  https://doi.org/10.1016/j.celrep.2026.117368
bioRxiv. 2026 May 12. pii: 2026.05.08.723786. [Epub ahead of print]

Lifestyle intervention is associated with attenuation of ER stress/inflammation and enhancement of naive immune cell identity in older adults with metabolic disease.

Rushil Yerrabelli, Asa Thibodeau, Djamel Nehar-Belaid, Radu Marches, Sathyabaarathi Ravichandran, Yoann Barnouin, Ranjan Sen, Silke Paust, Michael L Stitzel, Luigi Ferrucci, A Phillip West, Jacques Banchereau, Dennis T Villareal, George A Kuchel, Duygu Ucar.

Chronic inflammation and cellular stress are hallmarks of aging, obesity, and type 2 diabetes (T2D), but whether these programs can be modulated by lifestyle intervention in late life, particularly in the presence of established metabolic disease, remain unknown. We profiled circulating immune cells from older adults with obesity and T2D (ages 66-83 years; n = 9) before and after a 6-month lifestyle intervention combining caloric restriction with exercise training. Participants showed substantial weight loss (∼7%) alongside improvements in glycemic control, insulin sensitivity, and physical performance. Longitudinal single-cell transcriptomic and epigenomic profiling identified two major changes. First, intervention was associated with downregulation of inflammatory and endoplasmic reticulum (ER) stress transcriptional programs, with the most pronounced effects observed in CD14 + monocytes. DDIT3 (CHOP) was transcriptionally and epigenetically downregulated and its inferred regulatory network encompassed multiple inflammatory mediators. Second, naive CD4 + T, naive T reg , and naive B cells exhibited an upregulation of naive cell identity genes, with naiveness scores increasing after intervention, which declines with age in an independent healthy adult cohort. Together, these findings suggest that lifestyle intervention is associated with coordinated remodeling of both innate and adaptive immune compartments in older adults, revealing substantial plasticity of the aging immune system especially targeting ER stress, inflammation, and naive lymphocyte identity programs.

DOI: https://doi.org/10.64898/2026.05.08.723786
Transl Cancer Res. 2026 Apr 30. 15(4): 307

Identification and analysis of endoplasmic reticulum stress-related genes in neuroblastoma and construction of a prognostic gene signature.

Wenting Lu, Ruixi Zhou, Yan Yue, Junjie Ying, Tao Xiong, Jun Tang, Jing Shi, Hua Wang, Li Zhang, Tiechao Ruan.

   Background: Neuroblastoma (NB) is one of the most common malignant tumors in children. Despite intensive multimodal treatments, patients with high-risk NB still have a poor prognosis; therefore, early identification of high-risk patients based on reliable NB biomarkers is essential. Endoplasmic reticulum (ER) stress has been demonstrated to play a vital role in cancer biology; however, it is unclear whether ER stress-related genes are involved in NB and should be further explored as new potential diagnostic and prognostic targets.
Methods: We searched publicly available datasets with the aim to identify ER stress-related genes with a role in NB and establish a predictive model using ER stress-related signatures based on clinical information.
Results: Seventy-three ER stress-related genes were differentially expressed in NB cells; most of them were involved in biological processes such as intrinsic apoptotic signaling pathways and cellular responses to abiotic stimuli. Protein-protein interaction (PPI) analysis revealed hub genes, among which FN1 and MAPK8 were associated with the prognosis for patients with NB. A risk prediction model established based on 10 differentially expressed ER stress-related genes, including MAP2, PRKCD, MAPK8IP1, JPH1, TPP1, BCL2, EDN1, THBS1, MAPK8, and SERPINA3, could reliably identify patients with NB who had a high risk of poor prognosis.
Conclusions: Among the 73 ER stress-related genes differentially expressed in NB, the 2 hub and 10 risk prediction-related genes could potentially serve as therapeutic biomarkers and prognostic indicators for patients with NB.

Keywords:  ER stress-related gene signature; Endoplasmic reticulum stress (ER stress); disease risk model; neuroblastoma (NB)

DOI:  https://doi.org/10.21037/tcr-2025-1-2623
ACS Nano. 2026 May 27.

Endoplasmic Reticulum-Targeted Biomimetic Nanoparticles Potentiate the Immunotherapy of Triple-Negative Breast Cancer by Improving Immunogenicity and Eliminating Immune Resistance.

Shangui Liu, Cheng Zhang, Qixiang Feng, Jianbo Ji, Yuewu Xie, Yi Hao, Hailong Wang, Haining Tan, Guangxi Zhai.

  Low immunogenicity and immune resistance are insurmountable obstacles for triple-negative breast cancer (TNBC) immunotherapy. Here, we prepared endoplasmic reticulum membrane (EM)-coated, carrier-free nanoparticles (EM@CAJ) to simultaneously solve these obstacles. Benefiting from homologous EM decoration, EM@CAJ mainly relied on the intracellular endosome-Golgi-endoplasmic reticulum (ER) transport pathway, evading lysosomal degradation and achieving the precise delivery of drugs at the ER. At the ER site, chlorin e6 (Ce6) with laser irradiation induced efficient immunogenic cell death (ICD) via focused ROS-based ER stress, enhancing the immunogenicity of TNBC. However, this cascaded antitumor immune response inevitably caused immune resistance of the tumor through upregulating programmed cell death-1 ligand (PD-L1). JQ1 conveniently entered the adjacent cell nucleus and prevented induced PD-L1 production at the transcriptional level. Meanwhile, avasimibe (AVA) inhibited acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) at the ER and regulated cholesterol metabolism to accelerate existing PD-L1 degradation, which synergized with JQ1 to doubly eliminate immune resistance. Besides degrading PD-L1, the cholesterol metabolism regulation of AVA could also downregulate integrin αV expression to inhibit tumor metastasis. Therefore, by improving immunogenicity, eliminating immune resistance, and downregulating integrin αV, these synergistic therapeutic strategies efficiently inhibit primary tumor and pulmonary metastasis in orthotopic TNBC.

Keywords:  cancer immunotherapy; endoplasmic reticulum; cholesterol metabolism; immune resistance; immunogenic cell death

DOI:  https://doi.org/10.1021/acsnano.5c19913
Muscles. 2026 May 22. pii: 39. [Epub ahead of print]5(2):

Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.

Victoria C Sanfrancesco, Daniella Della Mea, David A Hood.

  To maintain homeostatic conditions and optimal function during stressors, mitochondria initiate retrograde signaling. The mitochondrial integrated stress response (ISR) and unfolded protein response (UPRmt) are critical quality control mechanisms activated during instances of mitochondrial perturbations. Restoration of mitochondrial homeostasis is orchestrated by three transcription factors, ATF4, CHOP, and ATF5, which upregulate protective genes to counteract stress. As the health and function of skeletal muscle are heavily dependent on a highly adaptive mitochondrial network, defining how mitochondrial health is maintained across various conditions is essential. Although several studies demonstrate the importance of these responses following instances of stress, the signaling mechanisms required to initiate such pathways remain poorly characterized in skeletal muscle. This review examines how the mitochondrial ISR/UPRmt and related transcription factors respond to organellar stress by emphasizing the molecular events that occur during exercise, aging and muscle disuse. By consolidating the literature, this work aims to highlight the current understanding of mitochondrial stress response signaling within skeletal muscle and thus emphasize areas for future research and potential therapeutic strategies during divergent metabolic conditions.

Keywords:  ATF4; ATF5; CHOP; adaptation; aging; exercise; integrated stress response; mitochondria; muscle inactivity; skeletal muscle; stress response; unfolded protein response

DOI:  https://doi.org/10.3390/muscles5020039