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Cells
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Endoplasmic Reticulum Stress Signaling Pathway: From Bench to Bedside
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Endoplasmic Reticulum Stress Signaling Pathway: From Bench to Bedside

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: 31 August 2025 | Viewed by 7187

Special Issue Editors

Dr. Samuel Stephens

E-Mail Website
Guest Editor
Department of Internal Medicine, FOE Diabetes Center, University of Iowa, Iowa City, IA, USA
Interests: β-cell function; insulin secretion; ER redox; golgi stress; mitochondrial metabolism
Dr. Jianchao Zhang

E-Mail Website
Guest Editor
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
Interests: Golgi apparatus; protein trafficking; ER redox; protein post-translational modification; SARS-CoV-2; viral assembly

Special Issue Information

Dear Colleagues,

The endoplasmic reticulum (ER) is the largest membrane organelle found in all eukaryotes and plays a central role in the oxidative folding of the majority of secretory and membrane proteins. To facilitate protein folding, the ER utilizes a number of folding enzymes and molecular chaperones, as well as oxidoreductases, which drive the formation of disulfide bonds to maintain stable protein structure. When the demand for protein folding exceeds the ER folding capacity, unfolded/misfolded proteins accumulate in the ER, leading to the activation of a signal transduction pathway known as the Unfolded Protein Response (UPR). The mammalian UPR consists of three branches (IRE1, PERK, and ATF6) that restore ER homeostasis by inhibiting protein synthesis, enhancing expression of folding enzymes and chaperones, and promoting clearance of non-native proteins. Physiologically, the balance between ER stress and the UPR is critical to maintaining healthy cell and tissue functions. However, prolonged ER stress and UPR activation can be maladaptive and ultimately lead to cellular dysfunction and death. Thus, in recent years, ER stress and the UPR have emerged as targets for drug development for major human diseases, including diabetes, cancer, infection, and neurodegenerative disorders.

This Special Issue seeks to unveil the molecular mechanisms through which cells respond to counter ER stress, explore the involvement of ER stress in the progression of diseases, and identify novel targets or molecules within the ER stress signaling pathway to treat human diseases.

Dr. Samuel Stephens
Dr. Jianchao Zhang
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • ER stress
  • oxidative protein folding
  • ER redox
  • ER calcium homeostasis
  • UPR
  • diabetes
  • cancer
  • virus

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Published Papers (4 papers)

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Research

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16 pages, 2344 KiB  
Article
In Vitro Inhibition of Endoplasmic Reticulum Stress: A Promising Therapeutic Strategy for Patients with Crohn’s Disease
by Bruno Lima Rodrigues, Lívia Bitencourt Pascoal, Lívia Moreira Genaro, Leonardo Saint Clair Assad Warrak, Beatriz Alves Guerra Rodrigues, Andressa Coope, Michel Gardere Camargo, Priscilla de Sene Portel Oliveira, Maria de Lourdes Setsuko Ayrizono, Lício Augusto Velloso and Raquel Franco Leal
Cells 2025, 14(4), 270; https://doi.org/10.3390/cells14040270 - 13 Feb 2025
Viewed by 2834
Abstract
Background: Crohn’s disease (CD) is an inflammatory bowel disease marked by an abnormal immune response and excessive pro-inflammatory cytokines, leading to impaired protein processing and endoplasmic reticulum (ER) stress. This stress, caused by the accumulation of misfolded proteins, triggers the unfolded protein response [...] Read more.
Background: Crohn’s disease (CD) is an inflammatory bowel disease marked by an abnormal immune response and excessive pro-inflammatory cytokines, leading to impaired protein processing and endoplasmic reticulum (ER) stress. This stress, caused by the accumulation of misfolded proteins, triggers the unfolded protein response (UPR) through IRE1/Xbp-1, PERK/eIF2α, and ATF6 pathways, which are linked to intestinal inflammation. This study aimed to investigate ER stress in CD patients’ intestinal mucosa and evaluate phenylbutyrate (PBA) as an ER stress inhibitor. Methods: Colon biopsies from CD patients and controls were cultured under five conditions, including 4-PBA treatments. Real-time PCR, cytokine level, and immunohistochemistry were performed. Results: Immunohistochemistry revealed that ER stress was activated in CD patients’ intestinal epithelial cells and lamina propria cells. PERK/eIF2α, but not IRE1/Xbp-1 or ATF6, was upregulated in CD patients compared to controls. UPR-related genes (STC2, CALR, HSPA5, HSP90B1) were also elevated in CD patients. PBA treatment significantly reduced ER stress and UPR markers while decreasing apoptotic markers like DDIT3. Pro-inflammatory cytokines, such as IL-1β, IL-6, IL-17, TNF- α, and sCD40L, were significantly reduced after PBA treatment. Conclusion: ER stress and UPR pathways are activated in CD colonic mucosa, and PBA reduces these markers, suggesting potential therapeutic benefits for CD-related inflammation. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress Signaling Pathway: From Bench to Bedside)
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Review

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33 pages, 2137 KiB  
Review
REDOX Imbalance and Oxidative Stress in the Intervertebral Disc: The Effect of Mechanical Stress and Cigarette Smoking on ER Stress and Mitochondrial Dysfunction
by Hui Li, Joshua Kelley, Yiqing Ye, Zhi-Wei Ye, Danyelle M. Townsend, Jie Zhang and Yongren Wu
Cells 2025, 14(8), 613; https://doi.org/10.3390/cells14080613 - 19 Apr 2025
Viewed by 551
Abstract
Low back pain is a widespread condition that significantly impacts quality of life, with intervertebral disc degeneration (IDD) being a major contributing factor. However, the underlying mechanisms of IDD remain poorly understood, necessitating further investigation. Environmental risk factors, such as mechanical stress and [...] Read more.
Low back pain is a widespread condition that significantly impacts quality of life, with intervertebral disc degeneration (IDD) being a major contributing factor. However, the underlying mechanisms of IDD remain poorly understood, necessitating further investigation. Environmental risk factors, such as mechanical stress and cigarette smoke, elevate reactive oxygen species levels from both endogenous and exogenous sources, leading to redox imbalance and oxidative stress. The endoplasmic reticulum (ER) and mitochondria, two key organelles responsible for protein folding and energy production, respectively, are particularly vulnerable to oxidative stress. Under oxidative stress conditions, ER stress and mitochondrial dysfunction occur, resulting in unfolded protein response activation, impaired biosynthetic processes, and disruptions in the tricarboxylic acid cycle and electron transport chain, ultimately compromising energy metabolism. Prolonged and excessive ER stress can further trigger apoptosis through ER–mitochondrial crosstalk. Given the unique microenvironment of the intervertebral disc (IVD)—characterized by hypoxia, glucose starvation, and region-specific cellular heterogeneity—the differential effects of environmental stressors on distinct IVD cell populations require further investigation. This review explores the potential mechanisms through which environmental risk factors alter IVD cell activities, contributing to IDD progression, and discusses future therapeutic strategies aimed at mitigating disc degeneration. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress Signaling Pathway: From Bench to Bedside)
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16 pages, 1519 KiB  
Review
Breaking the Feedback Loop of β-Cell Failure: Insight into the Pancreatic β-Cell’s ER-Mitochondria Redox Balance
by Amira Zaher and Samuel B. Stephens
Cells 2025, 14(6), 399; https://doi.org/10.3390/cells14060399 - 8 Mar 2025
Viewed by 1153
Abstract
Pancreatic β-cells rely on a delicate balance between the endoplasmic reticulum (ER) and mitochondria to maintain sufficient insulin stores for the regulation of whole animal glucose homeostasis. The ER supports proinsulin maturation through oxidative protein folding, while mitochondria supply the energy and redox [...] Read more.
Pancreatic β-cells rely on a delicate balance between the endoplasmic reticulum (ER) and mitochondria to maintain sufficient insulin stores for the regulation of whole animal glucose homeostasis. The ER supports proinsulin maturation through oxidative protein folding, while mitochondria supply the energy and redox buffering that maintain ER proteostasis. In the development of Type 2 diabetes (T2D), the progressive decline of β-cell function is closely linked to disruptions in ER-mitochondrial communication. Mitochondrial dysfunction is a well-established driver of β-cell failure, whereas the downstream consequences for ER redox homeostasis have only recently emerged. This interdependence of ER-mitochondrial functions suggests that an imbalance is both a cause and consequence of metabolic dysfunction. In this review, we discuss the regulatory mechanisms of ER redox control and requirements for mitochondrial function. In addition, we describe how ER redox imbalances may trigger mitochondrial dysfunction in a vicious feed forward cycle that accelerates β-cell dysfunction and T2D onset. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress Signaling Pathway: From Bench to Bedside)
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27 pages, 6291 KiB  
Review
Endoplasmic Reticulum Stress in Bronchopulmonary Dysplasia: Contributor or Consequence?
by Tzong-Jin Wu, Michelle Teng, Xigang Jing, Kirkwood A. Pritchard, Jr., Billy W. Day, Stephen Naylor and Ru-Jeng Teng
Cells 2024, 13(21), 1774; https://doi.org/10.3390/cells13211774 - 26 Oct 2024
Cited by 2 | Viewed by 1836
Abstract
Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity. Oxidative stress (OS) and inflammation are the major contributors to BPD. Despite aggressive treatments, BPD prevalence remains unchanged, which underscores the urgent need to explore more potential therapies. The endoplasmic reticulum (ER) plays [...] Read more.
Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity. Oxidative stress (OS) and inflammation are the major contributors to BPD. Despite aggressive treatments, BPD prevalence remains unchanged, which underscores the urgent need to explore more potential therapies. The endoplasmic reticulum (ER) plays crucial roles in surfactant and protein synthesis, assisting mitochondrial function, and maintaining metabolic homeostasis. Under OS, disturbed metabolism and protein folding transform the ER structure to refold proteins and help degrade non-essential proteins to resume cell homeostasis. When OS becomes excessive, the endogenous chaperone will leave the three ER stress sensors to allow subsequent changes, including cell death and senescence, impairing the growth potential of organs. The contributing role of ER stress in BPD is confirmed by reproducing the BPD phenotype in rat pups by ER stress inducers. Although chemical chaperones attenuate BPD, ER stress is still associated with cellular senescence. N-acetyl-lysyltyrosylcysteine amide (KYC) is a myeloperoxidase inhibitor that attenuates ER stress and senescence as a systems pharmacology agent. In this review, we describe the role of ER stress in BPD and discuss the therapeutic potentials of chemical chaperones and KYC, highlighting their promising role in future therapeutic interventions. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress Signaling Pathway: From Bench to Bedside)
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