bims-unfpre 2026-03-01 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–03–01
ten papers selected by
Susan Logue, University of Manitoba

H19 Is a PERK-Regulated Long Non-Coding RNA That Fine-Tunes UPR Signalling and Inhibits Endoplasmic Reticulum Stress-Induced Cell Death.
Unfolded Protein Response at the Crossroads: Integrating Endoplasmic Reticulum Stress with Cellular Stress Networks.
The Interplay Between Ca2+ Homeostasis, Endoplasmic Reticulum Stress, and the Unfolded Protein Response in Human Diseases.
Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function.
Atf6-/- mouse photoreceptors exhibit novel ciliary rootlet defect.
Inhibiting HSP27 activates the XBP1s/CerS1 interplay, which triggers DRP1-driven mitophagy, thereby protecting against cell death and promoting the KSHV lytic cycle in primary effusion lymphoma cells.
Tumor-derived Extracellular Vesicles Induce ER Stress to Drive Tolerogenic Dendritic Cell Development in the Tumor Microenvironment.
Pharmacological Inhibition of SLC33A1 Promotes Endoplasmic Reticulum Hyperoxidation and Induces Adaptive IRE1/XBP1s Signaling.
TAZ ( Wwtr1 ) deficiency leads to ER stress and mitochondrial dysfunction in a mouse model of Fuchs' endothelial corneal dystrophy.
Inhibition of IRE1α kinase increases ferroptosis resistance in triple-negative breast cancer cells.

Int J Mol Sci. 2026 Feb 08. pii: 1658. [Epub ahead of print]27(4):

H19 Is a PERK-Regulated Long Non-Coding RNA That Fine-Tunes UPR Signalling and Inhibits Endoplasmic Reticulum Stress-Induced Cell Death.

Wen Liu, Ananya Gupta, Michael Kerin, Sanjeev Gupta.

  The endoplasmic reticulum (ER) responds to stimuli that disrupts its homeostasis by activating a signalling network known as unfolded protein response (UPR), that restores cellular balance and determines cell fate through three key sensors: inositol-requiring enzyme 1α (IRE1α), activating transcription factor 6 (ATF6), and protein kinase RNA-like ER kinase (PERK). Emerging evidence suggests that UPR regulates the expression of numerous long non-coding RNAs (lncRNAs), which play critical roles in maintaining ER homeostasis. Here we show that expression of lncRNA H19 is downregulated in response to ER stress in (MCF7, T47D and 293T) cells. Using genetic and pharmacological approaches, we demonstrate that H19 downregulation is primarily mediated by the PERK arm of the UPR. Specifically, knockdown or chemical inhibition of PERK compromised the ER stress-mediated H19 repression, while PERK activation significantly reduced H19 expression. H19 overexpression promotes the optimal activation of ATF6 and PERK pathways, while it attenuates the signalling by IRE1-XBP1 axis of the UPR. Furthermore, in triple-negative breast cancer (TNBC) cells MDA-MB-231, ectopic H19 provided resistance to ER stress-induced apoptosis. Bioinformatic analyses across multiple breast cancer cohorts revealed that high H19 expression was associated with poor prognosis, particularly in basal-like subtypes. Collectively, our findings show that H19 is downregulated during UPR in a PERK-dependent manner, where H19 in turn modulates UPR signalling and cell fate during conditions of ER stress.

Keywords:  H19; breast cancer; cell death; endoplasmic reticulum stress; long non-coding RNA; triple negative breast cancer; unfolded protein response

DOI:  https://doi.org/10.3390/ijms27041658
Int J Mol Sci. 2026 Feb 19. pii: 1986. [Epub ahead of print]27(4):

Unfolded Protein Response at the Crossroads: Integrating Endoplasmic Reticulum Stress with Cellular Stress Networks.

Sebastian Gawlak-Socka, Edward Kowalczyk, Anna Wiktorowska-Owczarek.

  The endoplasmic reticulum (ER) is a central hub of cellular proteostasis, coordinating protein folding, lipid metabolism, calcium signaling, and inter-organelle communication. Disruptions in ER function activate the unfolded protein response (UPR), an evolutionarily conserved signaling network mediated by PERK, IRE1α, and ATF6. Initially viewed primarily as a stress-mitigating mechanism, the UPR is now recognized as a central coordinator of diverse cellular stress-response pathways. This review focuses on mechanistic insights into UPR signaling, with particular emphasis on its crosstalk with oxidative stress regulation, mitochondrial function and mitochondria-ER contact sites, autophagy, inflammatory signaling, and metabolic sensing. The analysis integrates evidence from biochemical and structural studies, genetic and pharmacological perturbation models, and selected in vivo investigations from PubMed and Google Scholar between 2000 and 2025, focusing on mechanistic, experimental and translational studies addressing UPR signaling and ER stress. Together, these studies demonstrate how transient UPR activation promotes cellular adaptation through coordinated transcriptional, translational, and organelle-specific responses. We further discuss how sustained or unresolved ER stress alters UPR outputs, shifting signaling toward maladaptive outcomes such as mitochondrial dysfunction, dysregulated autophagy, oxidative imbalance, and apoptosis. By placing the UPR within a network of interconnected stress pathways, this work provides a framework for understanding how ER proteostasis is linked to cell fate decisions under stress.

Keywords:  autophagy; endoplasmic reticulum stress; inflammation; metabolic stress; oxidative stress; unfolded protein response

DOI:  https://doi.org/10.3390/ijms27041986
Cells. 2026 Feb 15. pii: 352. [Epub ahead of print]15(4):

The Interplay Between Ca2+ Homeostasis, Endoplasmic Reticulum Stress, and the Unfolded Protein Response in Human Diseases.

Elia Ranzato, Simona Martinotti.

  The maintenance of endoplasmic reticulum (ER) Ca2+ homeostasis is intrinsically linked to the fidelity of protein folding, forming a functional tether that, when disrupted, triggers the Unfolded Protein Response (UPR). This bidirectional axis serves as a critical rheostat for cellular viability, yet its chronic dysregulation underpins the molecular etiology of numerous pathologies, including neurodegeneration, heart failure, and malignant transformation. This review provides a comprehensive interrogation of the Ca2+-ER Stress-UPR network, delineating how primary stress sensors-PERK, IRE1alpha, and ATF6-engage in complex feedback loops that either reinstate equilibrium or commit the cell to apoptosis. We specifically examine the PERK-CHOP-SERCA2b inhibitory circuit as a central driver of persistent Ca2+ depletion and discuss the role of Mitochondria-Associated Membranes (MAMs) in governing lethal Ca2+ transfer. Notably, we move beyond the classical paradigm of CHOP as a terminal apoptotic executioner, incorporating emerging evidence of its context-dependent adaptive functions. By synthesizing mechanistic insights across diverse disease models, this work highlights the transition from adaptive to maladaptive UPR as a universal pathological checkpoint. Ultimately, we evaluate the therapeutic potential of 'axis-targeted' interventions, such as SERCA activators and selective UPR modulators, aimed at resolving the underlying Ca2+ signaling defects in ER stress-related disorders.

Keywords:  ER stress; calcium dyshomeostasis; unfolded protein response (UPR)

DOI:  https://doi.org/10.3390/cells15040352
EMBO Mol Med. 2026 Feb 23.

Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function.

Catarina Perdigão, Josefa Torres, Helge M Magnussen, Janina Koch, Elena Rudashevskaya, Frederieke Moschref, Maksims Fiosins, Fritz Benseler, Sally Wenger, Tanja Nilsson, Sabine Beuermann, Stefan Bonn, Silvio O Rizzoli, Yogesh Kulathu, Olaf Jahn, Benjamin H Cooper, Mateusz C Ambrozkiewicz, JeongSeop Rhee, Nils Brose, Marilyn Tirard.

  Genetic variants that hinder post-translational protein modifications by UFM1, UFMylation, cause encephalopathies. UFMylation regulates endoplasmic reticulum (ER) homeostasis, but how UFMylation deficiencies cause selective neurological defects is unknown. Using murine UFM1-deficient neurons, we investigated two types of UFMylation pathologies, UFM1 loss and expression of a pathogenic UFM1-R81C variant. We found that UFM1-deficiency confounds neuron development and synapse function. Mechanistically, UFM1 loss is associated with induction of ER stress, activation of the unfolded protein response (UPR) pathway, and reduced protein translation. These defects are rescued by wild-type UFM1, but only partially by UFM1-R81C. UFM1-deficient and UFM1-R81C-expressing neurons display distinct responses to ER stress, indicating that UFM1-R81C is not merely a loss-of-function variant. Exploring therapeutic options, we show that Trazodone, an inhibitor of the UPR, restores protein translation solely in UFM1-R81C-expressing neurons, and increases synapse numbers in both UFM1-KO and UFM1-R81C-expressing neurons. Our study unveils a pivotal role for UFMylation in neuronal development, provides a molecular understanding of the signaling mechanisms altered in UFM1-associated encephalopathies, and offers important insights into potential treatments for these disorders.

Keywords:  Encephalopathies; Neuron; Synapse; UFM1; Unfolded Protein Response

DOI:  https://doi.org/10.1038/s44321-026-00389-6
bioRxiv. 2026 Feb 19. pii: 2026.02.18.701862. [Epub ahead of print]

Atf6-/- mouse photoreceptors exhibit novel ciliary rootlet defect.

Allyssa Bradley, Kristen Haggerty, Eun-Jin Lee, Michael A Robichaux, Jonathan H Lin.

ATF6 is a regulator of the Unfolded Protein Response that maintains cellular homeostasis during ER stress. In patients, ATF6 mutations cause photoreceptor dystrophy and sensorineural hearing loss. Atf6 -/- mice develop progressive hearing loss with stereocilia disorganization and mild retinal dysfunction, suggesting that ATF6 loss may impair the structural integrity of sensory cells. To test this possibility, we analyzed the retinal ultrastructure of Atf6 -/- mouse photoreceptors using transmission electron microscopy and identified a novel defect in which the ciliary rootlet is unbundled, disorganized, and possibly detached from the basal body. These findings demonstrate that ATF6 is essential for maintaining the structural organization of the photoreceptor ciliary apparatus, linking ER proteostasis to cytoskeletal integrity and providing a potential mechanistic basis for the progressive degeneration of photoreceptor outer segments and stereocilia observed in ATF6-deficient patients.

DOI: https://doi.org/10.64898/2026.02.18.701862
Cell Death Discov. 2026 Feb 26.

Inhibiting HSP27 activates the XBP1s/CerS1 interplay, which triggers DRP1-driven mitophagy, thereby protecting against cell death and promoting the KSHV lytic cycle in primary effusion lymphoma cells.

Roberta Gonnella, Vincenzo Corrado, Giulio Francesco Scaffidi, Rossella Benedetti, Michele Di Crosta, Roberta Zarrella, Maria Saveria Gilardini Montani, Roberta Santarelli, Mara Cirone.

PEL is an aggressive B-cell lymphoma that in the majority of cells harbors latent KSHV, although appropriate stimuli can induce viral replication. These include HDAC inhibitors such as butyrate, activation of endoplasmic reticulum (ER)/UPR stress, and exogenous administration of ceramide 18. These treatments reduce cell survival, but also activate adaptive branches of the UPR such as the Ire1α-XBP1s axis and/or trigger macroautophagy to counteract cell death, processes whose output may be manipulated by KSHV. HSPs are also upregulated by several cytotoxic treatments and support both cell survival and KSHV replication, suggesting a complex relationship between cell and viral fate. In this study, we demonstrate that HSP27 inhibition reduces PEL cell survival, activates ER stress including XBP1s, and upregulates CerS1, the enzyme that synthesizes ceramide 18. We further discovered a crosstalk between XBP1s and CerS1 that enhances protection against ER stress during HSP27 inhibition also promoting DRP1-dependent pro-survival mitophagy and triggers KSHV reactivation from latency. In conclusion this study suggests that HSP27 plays a previously unrecognized central role in controlling the UPR, CerS1 and mitochondrial autophagy, influencing both cell survival and KSHV lytic cycle in PEL cells.

DOI: https://doi.org/10.1038/s41420-026-02979-2
bioRxiv. 2026 Feb 12. pii: 2026.02.10.705213. [Epub ahead of print]

Tumor-derived Extracellular Vesicles Induce ER Stress to Drive Tolerogenic Dendritic Cell Development in the Tumor Microenvironment.

Xueying Wang, Michael P Plebanek, Y-Van Nguyen, Mahere Razazade Bazaz, Michael Sturdivant, Balamayooran Theivanthiran, Brent A Hanks.

Background: The efficacy of immune checkpoint blockade relies on the robust priming of T cells by immunostimulatory dendritic cells (DCs). However, the tumor microenvironment (TME) frequently drives DCs into a dysfunctional, pro-tolerogenic state governed by aberrant metabolic rewiring, creating a barrier to durable antitumor immunity. While tumor-derived extracellular vesicles (EVs) are abundant in the TME, their specific role in orchestrating this immunosuppressive metabolic reprogramming remains poorly understood. This study provides insight into the signaling axes through which tumor-derived EVs alter DC function and evaluates the therapeutic potential of targeting these pathways to overcome immunotherapy resistance.
Methods: Tumor models were engineered to express EV fluorescent markers to track tumor EV uptake in vivo . Bulk and single-cell RNA sequencing was integrated with multi-parameter flow cytometry to characterize the reprogramming of tumor EV-educated DCs both in vitro and in vivo . Western blotting, quantitative real-time polymerase chain reaction assays, various cellular metabolic assays, as well as T cell-based immunologic studies were utilized to characterize the underlying mechanisms of tumor EV-mediated DC reprogramming. DC-specific Ppara -deficient mice were developed to verify these mechanisms in vivo . PPAR-α targeted inhibitors were evaluated based on their ability to overcome checkpoint inhibitor resistance in an autochthonous model of melanoma.
Results: Tumor-derived EVs were found to promote tumor progression by suppressing host immunity. Further studies reveal that tumor-derived EVs induce a tolerogenic 'mregDC' transcriptional signature characterized by the upregulation of immunoregulatory molecules in DCs both in vitro and in vivo . These tumor EV-educated DCs exhibit an impaired capacity for CD8 + T cell priming, while demonstrating a proficiency for promoting CD4 + FoxP3 + regulatory T cell differentiation. Mechanistically, tumor EVs concurrently trigger the unfolded protein response (UPR) via the PERK-ATF4 and IRE1α-XBP1s signaling axes, subsequently activating the SREBP2 and PPAR-α transcription factors, respectively. This process drives both aberrant lipid accumulation and fatty acid oxidation (FAO) in DCs residing within the TME. DC-restricted ablation of PPAR-α significantly reversed the pro-tolerogenic effect of tumor EVs in vivo while pharmacologic targeting of PPAR-α overcomes anti-PD-1 resistance and augments CD8 + T cell infiltration in an autochthonous model of melanoma.
Conclusions: Tumor EVs contribute to the development and pro-tolerogenic function of mregDCs in the TME by triggering the UPR pathway. Aberrant lipid metabolism involving enhanced FAO are common characteristics associated with DC dysfunction in the TME. Strategies to interrupt these pathways represent promising approaches for reversing immune tolerance and enhancing tumor-targeted CD8 + T cell responses.

DOI: https://doi.org/10.64898/2026.02.10.705213
bioRxiv. 2026 Feb 18. pii: 2026.02.17.706344. [Epub ahead of print]

Pharmacological Inhibition of SLC33A1 Promotes Endoplasmic Reticulum Hyperoxidation and Induces Adaptive IRE1/XBP1s Signaling.

Sergei Kutseikin, Maria Rafiq, Prerona Bora, Shanshan Liu, Rick A Homan, Jeffrey T Mindrebo, Matthew Holcomb, H Michael Petrassi, Huang Qiu, Anastasiya Redkina, Justyna Sosna, Thanh-Trang Lee, Xiao Hu, Stefano Forli, Christopher G Parker, Gabriel C Lander, Kivanc Birsoy, Enrique Saez, R Luke Wiseman.

The endoplasmic reticulum (ER) transporter solute carrier family 33 member 1 (SLC33A1) has emerged as an attractive therapeutic target in etiologically diverse diseases, ranging from lung cancer to neurodegenerative disorders. Yet, no pharmacologic SLC33A1 modulators have been described. Here, we show that the small molecule IXA4, a highly selective activator of the adaptive IRE1/XBP1s signaling arm of the unfolded protein response (UPR), binds to SLC33A1 and inhibits its activity. Genetic depletion of SLC33A1 phenocopies the selective induction of IRE1/XBP1s signaling brought about by IXA4 treatment. Chemoproteomic analyses and cryo-electron microscopy show that IXA4 binds SLC33A1 within the central channel to inhibit transport of its substrate metabolite(s). Binding of IXA4 to SLC33A1 leads to the accumulation of oxidized glutathione within the ER, hyperoxidizing the ER lumen and inducing activation of adaptive IRE1/XBP1s signaling. Consistent with this function, we find that pharmacologic inhibition of SLC33A1 with IXA4 selectively reduces viability of KEAP1-deficient lung adenocarcinoma cells that have elevated levels of glutathione, mimicking the sensitivity of these cells to genetic deletion of SLC33A1. Our work demonstrates a new physiologic role of SLC33A1 in regulation of ER redox homeostasis and designates IXA4 as a pharmacologic inhibitor of SLC33A1 that can be used to evaluate the biological impact and therapeutic utility of SLC33A1 inhibition in homeostasis and in disease.

DOI: https://doi.org/10.64898/2026.02.17.706344
bioRxiv. 2026 Feb 19. pii: 2026.02.17.706456. [Epub ahead of print]

TAZ ( Wwtr1 ) deficiency leads to ER stress and mitochondrial dysfunction in a mouse model of Fuchs' endothelial corneal dystrophy.

Sangwan Park, Raneesh Ramarapu, Jaegook Lim, Sabina Khan, Meher J Khan, William R Stoehr, Brian C Leonard, Sara M Thomasy.

Fuchs' endothelial corneal dystrophy (FECD) impacts over 300 million individuals worldwide with corneal transplantation as the primary treatment. There is a dire need to establish non-surgical alternatives which are dependent on mouse models. Transcriptional co-activator with PDZ-binding motif (TAZ, encoded by Wwtr1 ) is a mechanotransducer implicated in maintaining homeostasis of corneal endothelial cells (CEnC). Wwtr1 -/- (TAZ KO) mice serve as an animal model for late-onset FECD. We combined single-cell transcriptomics, transmission electron microscopy, and immunofluorescence staining to elucidate the mechanisms driving pathogenesis in young (2-month-old) and geriatric (11-month-old) mice. A progressive stress response was observed in TAZ KOs defined by endoplasmic reticulum (ER) stress, mitochondrial structural and functional abnormalities, and impaired Na + /K + ATPase localization. These changes were accompanied by an altered expression of genes involved in extracellular matrix (ECM) organization, oxidative phosphorylation, macroautophagy and response to oxidative stress. Additionally, we noted age-related differences in cellular response with young TAZ KO CEnCs upregulating macroautophagy and downregulating ECM organization while geriatric TAZ KO CEnCs downregulated macroautophagy, and ECM organization. Both TAZ KO groups downregulated response to oxidative stress and cell-substrate adhesion. Together, these findings establish a mechanistic link between disrupted mechanotransduction and organelle stress in CEnC degeneration, further elaborating on potential mechanisms driving FECD pathogenesis. This positions TAZ KO mice as a translational platform for evaluating non-surgical therapeutic strategies targeting FECD.
Significance statement: Fuchs' endothelial corneal dystrophy (FECD) is a common, age-related cause of vision loss involving a depletion of corneal endothelial cells (CEnC) that necessitates corneal transplantation. Understanding why corneal endothelial cells progressively fail in this disease is essential for developing non-surgical therapies. Using transcriptomics, electron microscopy and immunofluorescence staining, we demonstrate that loss of the mechanotransducer TAZ disrupts cellular homeostasis by inducing endoplasmic reticulum stress, mitochondrial dysfunction and improper extracellular matrix and functional protein organization in CEnCs. By linking altered mechanotransduction to organelle stress and endothelial cell loss, these findings provide insight into fundamental disease mechanisms and identify pathways that may be targeted to preserve corneal endothelial function in FECD.

DOI: https://doi.org/10.64898/2026.02.17.706456
Oncol Lett. 2026 Apr;31(4): 130

Inhibition of IRE1α kinase increases ferroptosis resistance in triple-negative breast cancer cells.

Shuo Xu, Si-Qi Yang.

  Ferroptosis is a regulated form of cell death that serves a pivotal role in tumor suppression. Whilst the ribonuclease activity of inositol-requiring enzyme 1α (IRE1α) is associated with the regulation of ferroptosis, the potential involvement of its kinase domain in this process remains elusive. Thus, the present study aimed to investigate the specific role of the IRE1α kinase domain in regulating ferroptosis in breast cancer, particularly in the triple-negative breast cancer (TNBC) subtype. To this end, it employed a combination of bioinformatic analysis of clinical datasets, pharmacological inhibition of IRE1α kinase and genetic overexpression models in TNBC cell lines. The present study demonstrated that endoplasmic reticulum to nucleus signaling 1 (ERN1; the gene encoding IRE1α) was significantly downregulated in breast cancer compared with that in normal tissues, and that lower ERN1 levels were associated with a worse prognosis of patients with breast cancer. This association persisted in human epidermal growth factor receptor 2-positive and TNBC subtypes. In TNBC, IRE1α kinase inhibitors (APY29 and sunitinib) markedly inhibited ferroptosis induced by system Xc- inhibition. Moreover, by constructing overexpression models of wild-type IRE1α (IRE1α-WT) and a kinase-dead mutant (IRE1α-K599A), it was demonstrated that IRE1α-WT overexpression significantly enhanced sensitivity to ferroptosis, whereas the kinase-dead mutant had no significant effect. Mechanistically, IRE1α kinase inhibition upregulated solute carrier family 7 member 11 (also known as xCT) expression and promoted glutathione (GSH) synthesis, thereby suppressing ferroptosis. Collectively, the present study reveals a new function of IRE1α kinase in the regulation of ferroptosis, highlighting the critical regulatory role of the IRE1α kinase-xCT-GSH axis in ferroptosis in TNBC. Thus, IRE1α kinase may have potential as a therapeutic target.

Keywords:  ferroptosis; glutathione; inositol-requiring enzyme 1α; solute carrier family 7 member 11; triple-negative breast cancer

DOI:  https://doi.org/10.3892/ol.2026.15483