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New Insights into the Molecular Mechanisms of the UPR and Cell Stress

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 20 July 2026 | Viewed by 9008

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Dr. Quang Duy Trinh

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Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
Interests: infectious disease; medicine; viral infections in pregnancy
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Special Issue Information

Dear Colleagues,

The unfolded protein response (UPR) is a highly conserved cellular response that plays a crucial role in maintaining proteostasis under conditions of endoplasmic reticulum (ER) stress. UPR signaling, orchestrated by key branches such as PERK, ATF6, and IRE1, is essential for cell survival and adaptation. However, its dysregulation has been linked to a diverse array of diseases, including cancer, neurodegenerative disorders, metabolic syndromes, inflammatory conditions, and aging-related pathologies.

Beyond the UPR, cells face a variety of stressors, including oxidative stress, nutrient deprivation, hypoxia, etc., which activate both overlapping and unique molecular pathways that aim to restore homeostasis or trigger programmed cell death when damage is irreparable. These adaptive and maladaptive stress responses are intricately connected, with significant crosstalk between the UPR and other pathways such as autophagy, mitochondrial function, immune signaling, and apoptosis.

This Special Issue aims to provide novel insights into the molecular mechanisms underlying the UPR and other cellular stress responses in human biology and disease. We welcome original research articles, comprehensive reviews, and short communications that explore diverse aspects of this field, including, but not limited to, the following topics:

Mechanistic studies of UPR signaling pathways, including recent advances in our understanding of PERK, ATF6, and IRE1 activation and downstream effects.
Crosstalk between the UPR and other stress response pathways, including oxidative stress, mitochondrial dysfunction, inflammation, apoptosis, and autophagy.
The role of UPR and cellular stress in the pathogenesis of diseases such as cancer, neurodegenerative conditions, cardiovascular disorders, and metabolic syndromes.
Innovative therapeutic strategies targeting UPR-related pathways to modulate cellular stress responses for disease treatment.
The interplay between host cellular stress responses and microbial infections.
Emerging tools, techniques, and models, such as omics technologies, live-cell imaging, and computational approaches, for the study of UPR and cellular stress at molecular and cellular levels.
Context-dependent responses of the UPR and cell stress in specialized cells or tissues, highlighting its role in immunity, development, or tissue regeneration.

This Special Issue seeks to collect novel research and perspectives from molecular biology, biochemistry, systems biology, and translational research fields to deepen our understanding of how cells respond to diverse stressors. By integrating insights across disciplines, we aim to foster discussions on how UPR signaling and cellular stress responses can be harnessed to design novel therapeutic approaches for a wide spectrum of human diseases. We encourage contributions that explore not only the fundamental biology of these stress responses, but also their potential for clinical translation.

Dr. Quang Duy Trinh
Guest Editor

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Keywords

unfolded protein response
ER stress
oxidative stress
mitochondrial dysfunction
cell stress
stress response
UPR signaling pathway
immunity
inflammation
infection

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Published Papers (6 papers)

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Research

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20 pages, 2587 KB

Open AccessArticle

Deficiency of PTEN Confers Hypersensitivity to Fatty Acid-Mediated ER Stress in Transformed Hepatocytes

by Olaya Yassin, Odai Darawshi, Fangfang Wang, Youwei Zhang, Ata Abbas, William C. Merrick, William Cheung, Antony Antoniou, Shakti P. Pattanayak and Boaz Tirosh

Int. J. Mol. Sci. 2026, 27(6), 2778; https://doi.org/10.3390/ijms27062778 - 19 Mar 2026

Viewed by 442

Abstract

Deletion of the tumor suppressor gene phosphatase and tensin homolog (PTEN) in hepatocellular carcinoma (HCC) is associated with a poor response to therapy and reduced survival. In mice, the deletion of PTEN in hepatocytes generates steatosis; however, on the background of steatosis not all emerging HCC cells lack PTEN, suggesting that steatosis confers a metabolic liability to proliferating PTEN-deficient hepatocytes. Here, we show that PTEN-deficient HepG2 cells develop terminal stress in the endoplasmic reticulum (ER) and profound apoptosis when exposed to a mixture of oleic and palmitic acids, while control cells do not. Lipidomic analyses before and after the treatment indicate a higher increase in triglycerides in PTEN KO cells, as well as profound differences in phospholipid concentrations. Although the triglyceride content increases, the coalescence into lipid droplets was impaired in the KO cells, together with a reduction in β-oxidation. Xenograft studies showed that PTEN KO HCC tumors progressed faster than did the control tumors when mice were fed with normal chow and slower under a high-fat diet. We suggest that while the health risks of a fatty acid-rich diet to liver function and the increased propensity to develop HCC are prominent, once a PTEN-deficient HCC has been established, it exposes vulnerability to lipid overload that can be exploited through diet and pharmacological interventions. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of the UPR and Cell Stress)

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19 pages, 2357 KB

Open AccessArticle

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

by Wen Liu, Ananya Gupta, Michael Kerin and Sanjeev Gupta

Int. J. Mol. Sci. 2026, 27(4), 1658; https://doi.org/10.3390/ijms27041658 - 8 Feb 2026

Viewed by 721

Abstract

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. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of the UPR and Cell Stress)

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13 pages, 1240 KB

Open AccessArticle

Elevated MMP9 Expression—A Potential In Vitro Biomarker for COMPopathies

by Helen F. Dietmar, Ella P. Dennis, Francesca M. Johnson de Sousa Brito, Louise N. Reynard, David A. Young and Michael D. Briggs

Int. J. Mol. Sci. 2025, 26(24), 12070; https://doi.org/10.3390/ijms262412070 - 15 Dec 2025

Viewed by 678

Abstract

The intracellular retention of misfolded extracellular matrix proteins is a common disease mechanism in various rare skeletal diseases. This discovery has driven the study of ER stress and the unfolded protein response (UPR) as a promising therapeutic target in several skeletal dysplasias. In the case of COL10A1 mutations, targeting the UPR resulted in a clinical trial of the repurposed drug carbamazepine; however, for other closely related skeletal disorders, treatment with carbamazepine was ineffective, indicating the need for suitable markers for in vitro screenings of potential drug treatments. Mutations in cartilage oligomeric matrix protein (COMP), a cartilage structural protein, cause both multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH); together referred to as the COMPopathies, which result from the intracellular retention of mutant COMP to varying degrees. In contrast to other closely related skeletal disorders, caused by mutations in cartilage structural proteins, the involvement of the UPR is less clear, and so far, no common COMPopathy marker has been identified. Here, using cell models of COMPopathies, we identified MMP9 upregulation as a common feature of six pathogenic COMP variants that do not induce a prominent UPR. We further show that the archetypal p.V194D matrilin-3 MED variant (which causes MED) does not induce MMP9 expression, suggesting that MMP9 upregulation could serve as a specific marker of COMPopathies in vitro. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of the UPR and Cell Stress)

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Review

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17 pages, 1035 KB

Open AccessReview

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

by Sebastian Gawlak-Socka, Edward Kowalczyk and Anna Wiktorowska-Owczarek

Int. J. Mol. Sci. 2026, 27(4), 1986; https://doi.org/10.3390/ijms27041986 - 19 Feb 2026

Cited by 1 | Viewed by 1213

Abstract

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. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of the UPR and Cell Stress)

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26 pages, 2383 KB

Open AccessReview

The Role of Crosstalk Between the Unfolded Protein Response and Autophagy in Diseases Associated with Sympathetic Nervous System Imbalance: Mechanisms and Therapeutic Perspectives

by Bo Xu, Yi Yang and Renjun Wang

Int. J. Mol. Sci. 2026, 27(3), 1282; https://doi.org/10.3390/ijms27031282 - 27 Jan 2026

Viewed by 828

Abstract

Sympathetic nervous system (SNS) imbalance is a common pathological basis for cardiovascular diseases, non-alcoholic fatty liver disease, and diabetes. This review focuses on these diseases, analyzing two core mechanisms: excessive sympathetic excitation induced by endoplasmic reticulum stress (ERS) or autophagy dysfunction in key central nuclei (e.g., hypothalamus, rostral ventrolateral medulla); and ERS/autophagy abnormalities in peripheral target organs caused by chronic SNS overactivation. Existing studies confirm that chronic SNS overactivation promotes peripheral metabolic overload via sustained catecholamine release, inducing persistent ERS and disrupting the protective unfolded protein response (UPR)–autophagy network, ultimately leading to cell apoptosis, inflammation, and fibrosis. Notably, central ERS or autophagy dysfunction further perturbs autonomic homeostasis, exacerbating sympathetic overexcitation. This review systematically elaborates on SNS overactivation as a critical bridge mediating UPR–autophagy network dysregulation in central and peripheral tissues, and explores therapeutic prospects of targeting key nodes (e.g., chemical chaperones, specific UPR modulators, nanomedicine), providing a theoretical basis for basic research and clinical translation. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of the UPR and Cell Stress)

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23 pages, 2161 KB

Open AccessReview

Recent Advances in Engineering the Unfolded Protein Response in Recombinant Chinese Hamster Ovary Cell Lines

by Dyllan Rives, Tara Richbourg, Sierra Gurtler, Julia Martone and Mark A. Blenner

Int. J. Mol. Sci. 2025, 26(15), 7189; https://doi.org/10.3390/ijms26157189 - 25 Jul 2025

Cited by 4 | Viewed by 4209

Abstract

Chinese hamster ovary (CHO) cells are the most common protein production platform for glycosylated biopharmaceuticals due to their relatively efficient secretion systems, post-translational modification (PTM) machinery, and quality control mechanisms. However, high productivity and titer demands can overburden these processes. In particular, the endoplasmic reticulum (ER) can become overwhelmed with misfolded proteins, triggering the unfolded protein response (UPR) as evidence of ER stress. The UPR increases the expression of multiple genes/proteins, which are beneficial to protein folding and secretion. However, if the stressed ER cannot return to a state of homeostasis, a prolonged UPR results in apoptosis. Because ER stress poses a substantial bottleneck for secreting protein therapeutics, CHO cells are both selected for and engineered to improve high-quality protein production through optimized UPR and ER stress management. This is vital for optimizing industrial CHO cell fermentation. This review begins with an overview of common ER-stress related markers. Next, the optimal UPR profile of high-producing CHO cells is discussed followed by the context-dependency of a UPR profile for any given recombinant CHO cell line. Recent efforts to control and engineer ER stress-related responses in CHO cell lines through the use of various bioprocess operations and activation/inhibition strategies are elucidated. Finally, this review concludes with a discussion on future directions for engineering the CHO cell UPR. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of the UPR and Cell Stress)

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