bims-unfpre 2026-08-30 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–08–30
ten papers selected by
Susan Logue, University of Manitoba

Adaptive-to-maladaptive IRE1α signaling as a driver of amyloidogenic APP processing in Alzheimer's disease.
Targeting endoplasmic reticulum stress to attenuate cisplatin resistance in non-small cell lung cancer.
The dual role of Rpt3 in protecting cells from proteotoxic damage.
Functional Proteomics and Biological Screening of Protein Misfolding Under ER Stress Conditions in a Neuroblastoma Cell Model.
Fibroblast activation protein (FAP) promotes cardiac fibroblast activation in association with impaired ER-phagy.
Levels of ER Stress Markers GRP78, CHOP, and PERK in Cardiovascular Diseases.
Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Chronic Pain.
IRE1 activity is prognostic in localised and metastatic prostate cancer and affects epithelial lineage states.
DHCR24 Alleviates DNA Damage in Senescent Vascular Endothelial Cells via ENKUR/Ca2+ Signaling.
The ER-Golgi intermediate compartment: a central hub integrating membrane trafficking and stress responses.

Front Mol Biosci. 2026 ;13 1903849

Adaptive-to-maladaptive IRE1α signaling as a driver of amyloidogenic APP processing in Alzheimer's disease.

Daniel Wang, Qinan Yin.

  Alzheimer's disease (AD) is increasingly recognized as a disorder of proteostatic failure characterized by progressive disruption of neuronal protein quality control, culminating in amyloid-β (Aβ) accumulation and synaptic dysfunction. Chronic activation of the endoplasmic reticulum (ER) stress response represents one of the earliest molecular alterations detected in vulnerable brain regions and correlates with Braak progression before overt plaque deposition. Inositol-requiring enzyme 1 alpha (IRE1α), the most evolutionarily conserved sensor of the unfolded protein response (UPR), functions as a signaling rheostat within this network through its divergent downstream outputs. Under moderate proteotoxic stress, adaptive IRE1α- X-box binding protein 1 (XBP1) signaling supports ER proteostasis, preserves amyloid precursor protein (APP) quality control, and favors non-amyloidogenic α-secretase processing. Persistent ER stress, however, drives sustained IRE1α hyperactivation and engages regulated IRE1α-dependent decay (RIDD), which destabilizes microRNA (miRNA) networks that normally constrain beta-site APP-cleaving enzyme 1 (BACE1) expression, thereby favoring amyloidogenic APP processing. Accumulating evidence suggests that aging progressively compromises ER proteostatic capacity, thereby redirecting IRE1α signaling away from adaptive XBP1s-mediated responses toward a predominantly RIDD-driven state. This shift may reinforce a self-sustaining cycle in which accumulating Aβ further amplifies ER stress signaling. Here, we examine how dynamic changes in IRE1α signaling bias contribute to amyloidogenic progression in AD and consider whether selective modulation of adaptive versus maladaptive IRE1α outputs may offer stage-dependent therapeutic benefit.

Keywords:  APP processing; Alzheimer’s disease; BACE1; ER stress; IRE1α; RIDD; XBP1s; amyloid-β

DOI:  https://doi.org/10.3389/fmolb.2026.1903849
Med Oncol. 2026 Aug 24. pii: 254. [Epub ahead of print]43(10):

Targeting endoplasmic reticulum stress to attenuate cisplatin resistance in non-small cell lung cancer.

Semahat Celikten, Zafer Yildirim, Sevim Aydemir, Busra Bara, Eda Dogan, Zuhal Eroglu, Vildan Bozok.

  Cisplatin-based chemotherapy remains a cornerstone of treatment for advanced non-small cell lung cancer (NSCLC); however, the emergence of chemoresistance severely limits its clinical efficacy. Endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR) have been implicated in cancer cell survival and therapy resistance, highlighting modulation of this signalling as a potential therapeutic strategy. In this study, we investigated whether pharmacological induction of endoplasmic reticulum stress via sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibition could attenuate cisplatin resistance in NSCLC. Using parental and cisplatin-resistant cell lines, we demonstrate that thapsigargin induces transcriptional responses consistent with endoplasmic reticulum stress, characterised by dynamic regulation of GRP78, PERK, XBP1, and ATF4 mRNA expression. Notably, thapsigargin pre-treatment significantly reduced cisplatin IC₅₀ values and decreased resistance indices in resistant cells, indicating attenuation of the resistant phenotype. In addition, SERCA inhibition enhanced apoptotic cell death in selected models and markedly suppressed clonogenic survival and migratory capacity across all cell lines examined. Distinct UPR-related transcriptional patterns were observed between parental and resistant cells, suggesting adaptive remodelling of ER stress signalling during acquisition of cisplatin resistance. Collectively, these findings identify ER calcium homeostasis as a modifiable determinant of platinum responsiveness and support targeting ER stress pathways as a potential adjunct strategy to improve therapeutic efficacy in chemoresistant NSCLC.

Keywords:  ATF4; Cisplatin resistance; Endoplasmic reticulum stress; GRP78; Non-small cell lung cancer; PERK signalling; Thapsigargin; XBP1

DOI:  https://doi.org/10.1007/s12032-026-03369-5
FEBS J. 2026 Aug 29.

The dual role of Rpt3 in protecting cells from proteotoxic damage.

Ziting Zhu, Xiao Feng, Boyi Song, Hongzhen Zhu, Chunyi Lv, Qiaoqiao Zheng, Siyu Pan, Zheyu Fan, Zhiwei Huang, Ping Shi.

  Disrupted protein homeostasis is a shared characteristic in ageing, obesity-induced lipotoxicity and neurodegenerative diseases. The accumulation of misfolded or unfolded proteins within the cell triggers endoplasmic reticulum (ER) stress. In response, the unfolded protein response (UPR) and ER-associated degradation (ERAD) pathways are activated. A key mechanism to alleviate intracellular protein aggregation involves ubiquitination of substrates and their subsequent degradation by the proteasome. The ubiquitin-proteasome system (UPS) is indispensable for cellular protein quality control, and its dysfunction contributes to various proteopathies. However, the crosstalk between the proteasome subunit Rpt3 and the Ire1-Hac1 pathway appears to be rarely reported. In Saccharomyces cerevisiae, growth curve and spotting assay demonstrated that overexpression of Rpt3 reduced the sensitivity of ire1Δ or hac1Δ to ER stressors. The growth-promoting effect of Rpt3 is not a common feature of the BASE subunits, as overexpression of Rpt6 failed to rescue the growth inhibition. Deletion of hac1 resulted in stoichiometric imbalance among proteasomal subunits, which may be key for Rpt3-mediated rescue of hac1Δ growth, as deletion of the proteasome transcriptional factor Rpn4 impedes Rpt3 from restoring the growth of hac1Δ from ER stress. Overexpression of Rpt3 enhanced proteasome assembly and activity, reducing intracellular ubiquitin levels in hac1Δ. Moreover, Rpt3 increased the protein level of Hac1, and its alleviation of proteotoxic stress was dependent on the collaboration of ubiquitinating enzymes and chaperones. Western blot and proteasome activity assay in human cells confirmed the cross-species conservation of Rpt3 function. These results highlight a dual role for Rpt3 in proteostasis: beyond enhancing proteasomal activity, Rpt3 upregulates Hac1 protein abundance, thereby ensuring proteostasis maintenance.

Keywords:  Rpt3; endoplasmic reticulum stress; proteasome; proteostasis

DOI:  https://doi.org/10.1111/febs.70714
Curr Issues Mol Biol. 2026 Jul 29. pii: 772. [Epub ahead of print]48(8):

Functional Proteomics and Biological Screening of Protein Misfolding Under ER Stress Conditions in a Neuroblastoma Cell Model.

Adele Serra, Elva Morretta, Michela Pecoraro, Maria Chiara Monti, Maria Pascale, Silvia Franceschelli.

  Endoplasmic reticulum (ER) stress represents a critical pathophysiological condition that plays a central role in the development of various human diseases, including protein misfolding diseases. While the small molecule Vx-445 (Elexacaftor) exhibits robust cellular bioactivity, its cryptic intracellular targets and off-label mechanisms of action remain poorly defined. This study investigates the cytoprotective efficacy and molecular targets of Vx-445 in Thapsigargin-induced ER stress in a neuronal cell model. Integrating biochemical assays, gene expression proteomics, and label-free functional proteomics, we demonstrate that Vx-445 significantly mitigates oxidative stress by reducing intracellular levels of reactive oxygen species, restores calcium homeostasis to baseline levels, and prevents apoptosis by inhibiting cytochrome c release. These phenotypic modifications correlated with changes in proteomic expression and were validated by Drug Affinity Responsive Target Stability (DARTS) analysis to map restored cellular pathways and identify potential protein interaction partners. Together, these findings uncover alternative molecular targets for Vx-445, providing a mechanistic basis for drug repurposing strategies in endoplasmic reticulum stress-related diseases.

Keywords:  DARTs; ER stress; neurodegeneration; protein misfolding; proteomics

DOI:  https://doi.org/10.3390/cimb48080772
Biochem Biophys Res Commun. 2026 Aug 20. pii: S0006-291X(26)01216-7. [Epub ahead of print]834 154452

Fibroblast activation protein (FAP) promotes cardiac fibroblast activation in association with impaired ER-phagy.

Hong-Ju Huang, Qing-Shan Yang, Zhen-Fang Zhou, Chao Sun, Bing-Mei Zhu.

  Dilated cardiomyopathy (DCM) is characterized by progressive myocardial fibrosis and extracellular matrix remodeling, which severely impair cardiac function. The endoplasmic reticulum (ER) is essential for collagen synthesis, but the role of ER-phagy, a selective autophagy pathway that maintains ER proteostasis, in pathological cardiac fibroblast activation remains unclear. We integrated single-cell RNA-seq, bulk RNA-seq, and ATAC-seq datasets from human cardiac tissue and cultured human and rat cardiac fibroblasts. Key findings were validated in TGF-β-treated primary neonatal rat cardiac fibroblasts using siRNA-mediated FAP silencing and autophagy-associated assays. Fibroblast activation was accompanied by reduced expression and promoter accessibility of selected ER-phagy-related genes. An FAP-high activated fibroblast population showed a lower ER-phagy-related transcriptional signature. Integrated regulon and promoter-motif analyses linked FAP induction to a SMAD3-centered, BET-sensitive transcriptional program associated with repression of a subset of ER-phagy genes. FAP silencing attenuated fibroblast activation and ER stress and was accompanied by restored expression of selected ER-phagy-related transcripts and changes in autophagy-associated markers. These findings support a role for FAP in cardiac fibroblast activation and link its induction to altered ER-phagy-related proteostasis and ER stress.

Keywords:  Cardiac fibrosis; Chromatin remodeling; Dilated cardiomyopathy; Fibroblast activation protein

DOI:  https://doi.org/10.1016/j.bbrc.2026.154452
Int J Mol Sci. 2026 Aug 14. pii: 7246. [Epub ahead of print]27(16):

Levels of ER Stress Markers GRP78, CHOP, and PERK in Cardiovascular Diseases.

Tülay Oskay, Alten Oskay, Mert Özen, Isık Tekin, Fırat Okta, Abdo A Elfiky, Murat Seyit, Atakan Yılmaz, Hakan Akça, Ibrahim Türkçüer, Gergana Lengerova, Martina Bozhkova, Steliyan Petrov, Aylin Köseler.

  Cardiovascular diseases remain the leading cause of mortality worldwide, and endoplasmic reticulum (ER) stress has emerged as an important molecular mechanism underlying myocardial injury and heart failure. This study investigated the expression of the ER stress-related genes GRP78, PERK, and CHOP in peripheral whole blood obtained from patients with acute cardiovascular diseases. A total of 300 participants were enrolled, including 200 patients with ST-segment elevation myocardial infarction (STEMI, n = 55), non-ST-segment elevation myocardial infarction (NSTEMI, n = 88), decompensated heart failure (DHF, n = 40), or unstable angina pectoris (USAP, n = 17), and 100 healthy controls. Relative mRNA expression levels were quantified using quantitative real-time PCR. Intergroup comparisons were performed using the Kruskal-Wallis test followed by Dunn's post hoc test with Bonferroni adjustment. Significant differences in GRP78, PERK, and CHOP expression were observed among the study groups (all p < 0.001). GRP78 and PERK expression levels were highest in the STEMI and DHF groups, whereas CHOP expression was highest in the STEMI group. Significant positive correlations were identified between troponin and CHOP (r = 0.48), GRP78 (r = 0.42), and PERK (r = 0.39) (all p < 0.001), while weaker but significant associations were observed between inflammatory markers (CRP and NLR) and ER stress-related gene expression. Exploratory receiver operating characteristic (ROC) analysis showed that CHOP demonstrated the highest discriminatory performance for distinguishing patients with acute cardiovascular disease from healthy controls. These findings indicate that peripheral whole-blood ER stress-related gene expression is associated with acute cardiovascular disease and correlates with established biomarkers of myocardial injury and inflammation. Further prospective studies are required to determine the clinical significance of these findings.

Keywords:  CHOP; ER stress; GRP78; PERK; heart failure; myocardial infarction

DOI:  https://doi.org/10.3390/ijms27167246
Brain Sci. 2026 Aug 21. pii: 896. [Epub ahead of print]16(8):

Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Chronic Pain.

Arun Yadawa, Sufang Liu, Feng Tao.

  Chronic pain is a major global health burden and often remains difficult to treat with current therapies, which frequently provide incomplete relief and may cause systemic side effects. As essential organelles in eukaryotic cells, mitochondria facilitate ATP synthesis and serve as key regulators of calcium homeostasis and apoptosis. Evidence points to mitochondrial dysfunction not merely as a result of trauma, but as a fundamental factor in why pain becomes persistent. On the other hand, the endoplasmic reticulum (ER) is more than just a structural component of the cell; it is a multi-functional organelle responsible for protein quality control, including folding and degradation, as well as lipid production and calcium signaling. ER dysfunction is a primary driver of various pathologies, such as cardiovascular disease, cancer, and neurodegenerative disorders. The organelle's ability to execute its vital functions is strictly dependent on sufficient levels of ATP. Because mitochondrial and ER functions are closely interconnected through calcium exchange, ATP-dependent protein homeostasis, oxidative stress, and mitochondria-associated ER membranes, their dysfunction may act together to amplify nociceptive sensitization and pain chronification. In this review, we summarize current evidence linking mitochondrial dysfunction, ER stress, and ER-mitochondrial crosstalk to the pathogenesis of chronic pain and discuss their potentials as therapeutic targets.

Keywords:  chronic pain; endoplasmic reticulum stress; mitochondrial dysfunction; neuroinflammation; nociceptive sensitization; oxidative stress

DOI:  https://doi.org/10.3390/brainsci16080896
EMBO Mol Med. 2026 Aug 22.

IRE1 activity is prognostic in localised and metastatic prostate cancer and affects epithelial lineage states.

Dimitrios Doultsinos, Ingrid Tomljanovic, Eleftherios Pilalis, Sophia M Abusamra, Mohammed Alshalalfa, Romuald Parmentier, Vidhula Ahire, Imogen E Bridges, Sandy Figiel, Joanna Hester, Damien Leach, Ashwin Nandakumar, Rensheng Wan, Yanis Zekri, Jichang Zhang, Charlotte L Bevan, Edward O'Neill, Alastair D Lamb, Valentine Macauley, Jean Phillipe Theurillat, Alfonso Urbanucci, R Jeffrey Karnes, Daniel E Spratt, Elai Davicioni, David Quigley, Wilbert Zwart, Clementine Le Magnen, Aristotelis Chatziioannou, Ian G Mills.

Prostate cancer (PCa) is an androgen receptor (AR) driven, high-incidence disease significantly contributing to cancer mortality. To improve treatment outcomes for patients at high risk of metastasis, PCa is in need of better risk stratification at diagnosis. The unfolded protein response (UPR) is an AR-dependent process. However, the impact of the UPR transducer IRE1 on AR-dependent biology and acquired treatment resistance has not been defined. We use pre-clinical models of stress response to describe the impact of IRE1 activity loss on multiple PCa stages and demonstrate its involvement with poor prognosis (RB1 loss), and cell lineage determination (club-like phenotypes). Integrating clinical transcriptomic datasets, we chart IRE1 activity throughout PCa evolution and develop an IRE1 activity signature (IRE1sig1.0) reflecting both tumoral and micro-environmental stress responses. IRE1sig1.0 correlates with tumoral identity, and prognosticates localised and metastatic disease independently from AR activity. Using IRE1sig1.0 as a tool may inform ARSI suitability and guide IRE1 modulation as a novel combination therapeutic in prostate cancer.

DOI: https://doi.org/10.1038/s44321-026-00490-w
Aging Cell. 2026 Sep;25(9): e70688

DHCR24 Alleviates DNA Damage in Senescent Vascular Endothelial Cells via ENKUR/Ca2+ Signaling.

Han Li, Zhen Yang, Wukaiyang Liang, Jie Huang, Tianyi Ji, Hao Nie, Zixin Wan, Yuqi Qiu, Yi Huang, Le Zhang, Cuntai Zhang, Jinhua Yan.

  DNA damage is considered one of the major contributors to aging. DHCR24, a multifunctional enzyme located within the endoplasmic reticulum (ER), is closely related to DNA damage. Our previous study showed that DHCR24 could delay vascular endothelial cells (ECs) senescence. The relationship between DHCR24 and DNA damage during ECs senescence requires further investigation. Here, we demonstrate that aging activates ATM-mediated DNA damage response (DDR) in human umbilical vein endothelial cells (HUVECs) and mouse pulmonary microvascular endothelial cells (PMVECs), and DHCR24 expression is downregulated. Knocking down DHCR24 in young HUVECs induces the activation of ATM-mediated DDR, which has been confirmed in PMVECs of DHCR24 endothelial-specific knockout mice. Consistently, RNAseq indicated that DHCR24 was essential for cell cycle regulation. Further investigations revealed that both replicatively senescent HUVECs and young HUVECs with DHCR24 knockout exhibited ER stress and mitochondrial dysfunction, which might be attributable to calcium overload resulting from DHCR24 deficiency. In this pathological process, the DHCR24-deficiency-induced upregulation of ENKUR markedly exacerbates calcium overload. Conversely, ENKUR knockdown not only alleviates the ER stress and mitochondrial dysfunction caused by DHCR24 inhibition, but also suppresses the ATM-mediated DDR. Moreover, DHCR24 overexpression reduces the elevated ENKUR levels and simultaneously mitigates DOX-induced calcium overload in HUVECs. Collectively, these findings identify DHCR24-ENKUR-dependent Ca2+ signaling as a mechanism linking ER-mitochondrial homeostasis to endothelial DNA damage and senescence. Accordingly, restoring DHCR24 function or regulating calcium signal transduction through this pathway may hold therapeutic potential for delaying vascular ECs senescence and preventing age-related diseases.

Keywords:  3β‐hydroxysterol δ 24 reductase; Ca2+ overload; DNA damage response; endoplasmic reticulum stress; mitochondrial dysfunction; vascular endothelial cell senescence

DOI:  https://doi.org/10.1111/acel.70688
EMBO Rep. 2026 Aug 22.

The ER-Golgi intermediate compartment: a central hub integrating membrane trafficking and stress responses.

Yingying Guo, Jianfei Zheng, Lei Liu, Shulin Li, Min Zhang, Liang Ge.

The endoplasmic reticulum-Golgi intermediate compartment (ERGIC) is a dynamic membrane system at the ER-Golgi interface, traditionally viewed as a transient station for COPII- and COPI-dependent trafficking. Emerging evidence redefines the ERGIC as a stress-responsive regulatory hub that integrates membrane trafficking with cellular adaptation. In addition to coordinating bidirectional transport and cargo sorting, the ERGIC actively participates in protein quality control during ER stress and remodels trafficking flux under perturbations. It serves as a platform linking secretory pathways to stress signaling, contributing to autophagosome biogenesis, facilitating unconventional protein secretion under stress conditions, and modulating innate immune responses, including STING activation. The ERGIC is also co-opted by pathogens such as coronaviruses, underscoring its role at the interface of membrane remodeling and host defense. These functions position the ERGIC as a central integrator of trafficking dynamics and stress responses, whose structural plasticity enables rapid adaptation to physiological and pathological challenges.

DOI: https://doi.org/10.1038/s44319-026-00908-z