bims-unfpre 2025-10-19 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–10–19
ten papers selected by
Susan Logue, University of Manitoba

The Role of Endoplasmic Reticulum Stress in the Development of Periodontitis-From Experimental Cell and Animal Models to Humans.
Immunoregulatory Functions of the ER Stress Sensor IRE1 in Myeloid Cell Biology.
ISRIB inhibits endoplasmic reticulum stress to ameliorate chronic restraint stress-induced intestinal inflammation.
The Role of Endoplasmic Reticulum Stress and Unfolded Protein Response in Gynecological Cancers: A Narrative Review.
ER Stress Ire1-Xbp1s Pathway Maintains Youthful Epidermal Basal Layer Through the Regulation of Cell Proliferation.
Robinin attenuates cardiac oxidative stress-induced endoplasmic reticulum-dependent apoptosis through AKT/GSK3β pathway.
Stress, plasticity, and fibrosis: unfolding the role of the IRE1α/RIDD/Fgfr2 axis.
Endoplasmic reticulum stress orchestrates tumor metabolism and immunity: new insights into immunometabolic therapeutics.
Unique and Conserved Endoplasmic Reticulum Stress Responses in Neuroendocrine Cells.
Anti-proliferative effects of novel T-type calcium channel blocker KCP10043F in human pancreatic cancer cells through Ca2+/CaMKII pathway via ER stress induction.

Int J Mol Sci. 2025 Oct 02. pii: 9620. [Epub ahead of print]26(19):

The Role of Endoplasmic Reticulum Stress in the Development of Periodontitis-From Experimental Cell and Animal Models to Humans.

Sebastian Gawlak-Socka, Paulina Sokołowska, Gabriela Henrykowska, Edward Kowalczyk, Sebastian Kłosek, Anna Wiktorowska-Owczarek.

  Periodontal disease is a prevalent inflammatory disorder that can lead to severe oral complications. Recent studies increasingly underline the role of endoplasmic reticulum (ER) stress in its pathogenesis. Experimental models using inflammatory agents such as lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-α), and ligature-induced periodontitis in rodents, as well as chemical hypoxia, have consistently demonstrated the activation of unfolded protein response (UPR) pathways in periodontal cells. Key ER stress markers, including CHOP, GRP78, PERK, and ATF6, were upregulated in periodontal ligament cells, stem cells, and gingival epithelial cells under these conditions. While ER stress in periodontitis is primarily associated with detrimental outcomes such as apoptosis and inflammation, it may also have a physiological role in bone remodeling via the PERK-eIF2α-ATF4 axis. Importantly, several ER stress-modulating agents-such as oridonin, melatonin, and exosomes derived from M2 macrophages-have shown therapeutic potential by reducing stress marker expression and limiting periodontal damage. These findings suggest that targeting ER stress may offer a novel therapeutic strategy. Future human studies are essential to determine whether a combined approach targeting inflammation and ER stress could more effectively halt or reverse periodontal tissue destruction, while also assessing the long-term safety of ER stress modulation.

Keywords:  ER stress; UPR pathway; periodontitis

DOI:  https://doi.org/10.3390/ijms26199620
J Leukoc Biol. 2025 Oct 17. pii: qiaf145. [Epub ahead of print]

Immunoregulatory Functions of the ER Stress Sensor IRE1 in Myeloid Cell Biology.

Alonso Lira, Javier López, Fabiola Osorio.

  Myeloid cells- including monocytes, macrophages, dendritic cells (DCs), and granulocytes constitute a versatile arm of the immune system, serving as frontline sentinels that detect and react to environmental cues and orchestrate tailored immune responses. Their ability to respond promptly to distinct threats depends on dynamic processes that include differentiation, antigen presentation, and secretion of pro-inflammatory and antimicrobial mediators. These functions are tightly linked to the integrity of the endoplasmic reticulum (ER), an essential organelle responsible for the synthesis, folding, and modification of proteins involved in immune signaling. Disruption of ER homeostasis is commonly induced by infection, inflammation, autoimmunity, or cancer settings, leading to ER stress and activation of the unfolded protein response (UPR), a three-pronged signaling pathway aiming to restore the fidelity of the cellular proteome. Among UPR branches, the IRE1/XBP1 pathway has emerged as a central regulator of myeloid cell function, integrating proteostatic stress with immune modulation. Despite growing evidence positioning the IRE1/XBP1s axis as a pivotal immunological target bearing biomedical potential, the context-dependent outcomes of this UPR branch in myeloid cells, ranging from protective to maladaptive, remain incompletely understood. In this review, we explore the multifaceted roles of IRE1 in shaping myeloid cell responses across physiological and pathological states, highlighting molecular mechanisms and their impact on immune homeostasis and disease pathogenesis.

Keywords:  IRE1; Unfolded protein response; XBP1; homeostasis; infections; myeloid cells; pathology

DOI:  https://doi.org/10.1093/jleuko/qiaf145
Eur J Pharmacol. 2025 Oct 10. pii: S0014-2999(25)00990-2. [Epub ahead of print]1007 178236

ISRIB inhibits endoplasmic reticulum stress to ameliorate chronic restraint stress-induced intestinal inflammation.

Lihua Xie, Wenyan Zhou, Yan Tang, Yan Yi, Wenyu Cao, Xiaolin Zhong, Ling Chen.

  Prolonged psychological stress can cause intestinal barrier dysfunction, increasing its permeability and allowing harmful substances present in the gut, such as bacteria and toxins, to readily traverse the intestinal barrier and enter the bloodstream, ultimately precipitating systemic inflammation. This study used the chronic restraint stress (CRS) model to stimulate intestinal inflammation induced by prolonged psychological stress in humans. Endoplasmic reticulum (ER) stress is closely linked to intestinal diseases. Unresolved and persistent ER stress can damage the intestinal barrier, activating inflammation through the unfolded protein response, leading to intestinal diseases, such as inflammatory bowel disease and irritable bowel syndrome. By examining proteins associated with the PERK pathway, upregulated levels of PERK, P-eIF2α, and C/EBP homologous proteins were observed in the jejunum and colon during CRS-induced intestinal inflammation. Integrated stress response inhibitor (ISRIB), a potent inhibitor of the PERK pathway, plays a crucial role in suppressing integrated stress responses. Herein, ISRIB ameliorated CRS-induced jejunal and colonic mucosal injury and barrier dysfunction by inhibiting ER stress. Prolonged ER stress exposure can lead to the onset of cellular apoptosis. ISRIB effectively prevented the upregulation of CRS-induced apoptosis markers (Caspase-3, Bax/Bcl-2) in the jejunum and colon. Furthermore, ISRIB intervention reversed the CRS-induced elevation of NLRP3 inflammasome and pyroptosis marker GSDMD in the jejunum and colon. Therefore, ISRIB has emerged as a promising therapeutic candidate for treating intestinal inflammation related to prolonged psychological stress.

Keywords:  CRS; ER stress; ISRIB; Intestinal inflammation

DOI:  https://doi.org/10.1016/j.ejphar.2025.178236
Cureus. 2025 Oct;17(10): e94434

The Role of Endoplasmic Reticulum Stress and Unfolded Protein Response in Gynecological Cancers: A Narrative Review.

Stefanos Flindris, Konstantinos Flindris, Spyros Foutadakis, Michail Kalinderis, Alexandros Traianos, Vassiliki I Kigka, Freideriki Nteka, George Mpourazanis, Ioanna Styliara, Effrosyni Styliara, Panagiotis Tsirkas, Stamatios Petousis, Chrysoula Margioula-Siarkou, Iordanis Navrozoglou.

  The unfolded protein response (UPR) mediated by IRE1/XBP1, PERK/eIF2α/ATF4, and ATF6/GRP78 governs tumor adaptation to hypoxia, nutrient deprivation, and therapy stress. In gynecologic malignancies (ovarian, endometrial, cervical), persistent endoplasmic reticulum (ER)-stress signaling underlies proliferation, invasion, immune evasion, and treatment resistance but also creates druggable liabilities. We conducted a narrative review of peer-reviewed literature indexed in MEDLINE (PubMed), Embase, Scopus, and Web of Science from inception through 13 September 2025. Search terms combined ER-stress/UPR pathways with gynecologic cancers. Eligible records included recent and high-quality preclinical, translational, and clinical studies, clinical trials, and high-quality reviews focused on UPR biology, biomarkers, or therapeutics. Data were synthesized by disease site and UPR branch. Across tumor types, UPR activation correlates with aggressive phenotypes and poorer outcomes. In epithelial ovarian cancer, GRP78/ATF6/PERK overexpression associates with inferior survival and chemoresistance, supporting their utility as biomarkers and therapeutic targets. Endometrial cancer demonstrates UPR gene-signature stratification of prognosis and immune infiltration, suggesting risk-adapted strategies. Cervical cancer leverages PERK/IRE1 signaling for therapy tolerance and dormancy. The tumor-immune interface is UPR-sensitive: CHOP and myeloid IRE1α signaling can dampen antitumor immunity, providing a rationale to pair UPR modulation with immunotherapy. Therapeutically, IRE1 RNase inhibitors (e.g., MKC-8866, B-I09), PERK/EIF2AK3 pathway modulators, protein-disulfide isomerase inhibition, and agents that trigger irrecoverable ER stress show preclinical efficacy, including synergy with platinum, poly (ADP-ribose) polymerase (PARP) inhibitors, HDAC6 blockers, and PD-1 inhibitors. Early clinical efforts investigating ER-stress-modulating combinations in platinum-resistant ovarian cancer highlight translational promise but remain preliminary. Thus, ER-stress/UPR signaling is a convergent, targetable axis in gynecologic cancers. Priorities include validating UPR-based prognostic signatures, defining context-specific vulnerabilities (e.g., genotype-informed IRE1/XBP1 dependence), and executing biomarker-driven clinical trials that combine UPR-targeted agents with standard chemotherapy, PARP inhibition, and immunotherapy to overcome resistance and improve patient outcomes.

Keywords:  atf6/grp78; cervical cancer; endometrial cancer; er stress; gynecologic oncology; ire1/xbp1; ovarian cancer; perk/eif2α/atf4; targeted therapy; unfolded protein response

DOI:  https://doi.org/10.7759/cureus.94434
Aging Cell. 2025 Oct 12. e70258

ER Stress Ire1-Xbp1s Pathway Maintains Youthful Epidermal Basal Layer Through the Regulation of Cell Proliferation.

Daniel Semmy, Kota Abe, Mizuki Honda, Hiroko Omori, Shohei Ogamino, Tobias Clausen Mercurio, Kyosuke Asakawa, Emi K Nishimura, Shinya Oki, Yasuyuki Ohkawa, Tohru Ishitani.

  The endoplasmic reticulum (ER) stress-response is an adaptive cellular mechanism activated by an accumulation of unfolded proteins within the ER. Although recent evidence shows that the ER stress-response is activated in aged tissues, and therefore ER stress is considered a candidate driver of aging, the spatiotemporal regulation and roles of the ER stress-response during aging remain unclear. To address this research gap, we introduced an Ire1-Xbp1s ER stress-response pathway-sensitive reporter into the ultra-short-lived vertebrate Nothobranchius furzeri that allows for the analysis of its aging processes within a short period of time. Using this reporter in N. furzeri, we confirmed the previously reported age-dependent activation of ER stress in various tissues and identified an unexpected role of the Ire1-Xbp1s ER stress-response pathway in regulating epidermal tissue homeostasis and aging. The Ire1-Xbp1s ER stress-response pathway is active in the young epidermal basal layer but declines with aging. Photo-isolation chemistry-based spatial transcriptomics and functional assays revealed that the Ire1-Xbp1s pathway maintains young epidermal cell proliferation by activating the cell cycle regulator Vcp, whereas the age-dependent decline in glucose metabolism reduces Ire1-Xbp1s activity, consequently downregulating cell proliferation. Collectively, our study elucidates a previously unidentified role of the ER stress-response in skin aging, which can offer insights into therapeutic targets for promoting healthy skin.

Keywords:  Ire1 protein; cell proliferation; endoplasmic reticulum stress; skin aging; unfolded protein response

DOI:  https://doi.org/10.1111/acel.70258
Sci Rep. 2025 Oct 15. 15(1): 36097

Robinin attenuates cardiac oxidative stress-induced endoplasmic reticulum-dependent apoptosis through AKT/GSK3β pathway.

N Abhirami, V A Aswathy, Janeesh Plakkal Ayyappan.

  Myocardial injury is a pathological condition often resulting from excessive β-adrenergic stimulation, such as that induced by isoproterenol (ISO), a β-adrenergic agonist that increases reactive oxygen species (ROS) production, leading to endoplasmic reticulum (ER) stress, apoptosis, and impaired survival signaling. This study investigated Robinin's (Rob) ability to mitigate ISO-induced myocardial damage in H9c2 cardiomyocytes and male Sprague-Dawley rats. ISO-induced damage was assessed through histology, oxidant/antioxidant assays, cardiac marker enzyme assays, and molecular analyses, including PCR and Western blotting. Rob treatment significantly reduced ISO-induced ROS generation and apoptosis, while preserving cell morphology and survival. Rob also modulated ER stress and apoptosis-related proteins, restoring cardiomyocyte function in a dose-dependent manner. Western blot analysis confirmed Rob's inhibition of ER stress-mediated apoptosis in both in vitro and in vivo models. These findings suggest that Rob exerts potent cardioprotective effects by reducing oxidative stress, modulating ER stress, and inhibiting apoptosis. Its ability to restore ER function and cardiomyocyte viability highlights its potential as a therapeutic agent for ISO-induced myocardial damage.

Keywords:  Cardio protection; ER stress; Myocardial infarction; Rob; Therapeutic agent

DOI:  https://doi.org/10.1038/s41598-025-20063-0
J Clin Invest. 2025 Oct 15. pii: e196740. [Epub ahead of print]135(20):

Stress, plasticity, and fibrosis: unfolding the role of the IRE1α/RIDD/Fgfr2 axis.

SeungHye Han.

Recent advances in sequencing technologies have enabled the identification of intermediate cell states during alveolar epithelial differentiation, which expand during repair following injury and in fibrotic lungs. Although ER stress has been implicated in pulmonary fibrosis, the underlying mechanisms remain elusive. The featured study by Auyeung and colleagues looked for links between the unfolded protein response sensor inositol-requiring enzyme 1α (IRE1α), intermediate epithelial cell states, and fibrotic remodeling in the lung. They identified Regulated IRE1-Dependent Decay (RIDD) as a key effector of IRE1α signaling that drives differentiation of alveolar epithelial type 2 cells to damage-associated intermediate cells and contributes to pulmonary fibrosis, likely by degrading Fgfr2 mRNA. These findings unveil therapeutic targets and open new avenues for investigating the interplay between cellular stress responses, epithelial differentiation, and fibrotic disease.

DOI: https://doi.org/10.1172/JCI196740
Front Immunol. 2025 ;16 1674163

Endoplasmic reticulum stress orchestrates tumor metabolism and immunity: new insights into immunometabolic therapeutics.

Zhang Fu, Mengyue Li, Huaixiang Zhou, Xin Zhong, Zhiqiang Zhang, Xianwen Meng, Youheng Jiang, Tao Wang, Ningning Li.

  Endoplasmic reticulum (ER) stress and its adaptive signaling network have emerged as central regulators of tumor progression, metabolic rewiring, and immune modulation. Within the nutrient-deprived and hypoxic tumor microenvironment, ER stress reprograms glucose, lipid, and amino acid metabolism, exerting context-dependent effects that influence both tumor cell viability and immune regulation. Concurrently, ER stress remodels the metabolic fitness and functional states of immune cells, influencing T cell exhaustion, macrophage polarization, and dendritic cell maturation. Emerging evidence indicates that tumor- and immune-cell-derived metabolites (e.g., lactate, fatty acids, and tryptophan derivatives) exert both metabolic and immunomodulatory functions, thereby shaping a dynamic "ER stress-metabolism-immunity" axis that underlies cancer heterogeneity, immune evasion, and therapeutic resistance. In this review, we synthesize recent advances delineating how canonical ER stress pathways intersect with immunometabolic reprogramming across tumor and immune compartments, and we discuss how this integrated axis reshapes the tumor immune microenvironment (TIME). Targeting this integrated axis may unveil new strategies to overcome metabolic vulnerabilities and enhance the efficacy of immunotherapy.

Keywords:  endoplasmic reticulum stress; immunometabolism; metabolic reprogramming; tumor immune microenvironment; unfolded protein response

DOI:  https://doi.org/10.3389/fimmu.2025.1674163
Cells. 2025 Sep 30. pii: 1529. [Epub ahead of print]14(19):

Unique and Conserved Endoplasmic Reticulum Stress Responses in Neuroendocrine Cells.

Karina Rodrigues-Dos-Santos, Gitanjali Roy, Anna Geisinger, Sahiti Somalraju, Travis S Johnson, Michael A Kalwat.

  Endocrine cells are dedicated to the production and processing of hormones, from peptides to small molecules, to regulate key physiological processes, including glucose homeostasis and metabolism. Because of this relatively high productivity, endocrine cells must handle a variety of stresses from oxidative stress to the unfolded protein response of the endoplasmic reticulum (UPRER). While much is known about the major pathways regulating the UPRER, the roles of endocrine cell type-specific, context-dependent, and time-dependent transcriptional changes are not well explored. To identify unique and shared responses to the UPRER across a subset of endocrine cell types, we tested representative lines for β-cells (insulin), α-cells (glucagon), δ-cells (somatostatin), X/A-cells (ghrelin), L-cells (glucagon-like peptide 1 (GLP1)), and thyrotropes (thyroid hormone and thyroglobulin). We exposed each cell type to the canonical ER stressor thapsigargin for 6 and 24 h, or vehicle for 24 h, and performed mRNA sequencing. Analysis of the data showed all lines responded to thapsigargin. Comparisons of differentially expressed genes between each line revealed both shared and unique transcriptional signatures. These data represent a valuable mineable set of candidate genes that may have cell type-specific functions during the UPRER and have the potential to lead to a new understanding of how different endocrine cells mitigate or succumb to ER stress.

Keywords:  ER stress; computational biology; endocrinology; hormone secretion

DOI:  https://doi.org/10.3390/cells14191529
Life Sci. 2025 Oct 10. pii: S0024-3205(25)00619-8. [Epub ahead of print]382 123983

Anti-proliferative effects of novel T-type calcium channel blocker KCP10043F in human pancreatic cancer cells through Ca2+/CaMKII pathway via ER stress induction.

Gi-Hui Kim, Jeong-Hun Lee, Kyung-Sook Chung, Ko-Beom Seo, Jin-Won Hong, Seung-Jun Yun, Jae-Yeol Lee, Kyung-Tae Lee.

  Pancreatic cancer is among the most lethal cancer types with a 5-year survival rate of approximately 5 %. Although a T-type calcium channel blocker, 4-(4-fluorobenzylcarbamoylmethyl)-3-(4-cyclohexylphenyl)-2-[3-(N,N-dimethylureido)-N'-methylpropylamino]-3,4-dihydroquinazoline (KCP10043F, OZ-001), previously exhibited the anti-tumor effects in lung cancer, its anti-proliferative effects and the specific molecular mechanisms in pancreatic cancer remain unclear. This study was conducted to evaluate the anti-proliferative effects of KCP10043F on human pancreatic cancer cell lines, PANC-1 and MIA PaCa-2. 1) KCP10043F suppressed cell growth and colony formation, and promoted the G1 phase cell retention by downregulating G1 phase-related proteins; 2) KCP10043F triggered apoptotic cell death via the intrinsic pathway by upregulating BH3-only Bcl-2 family proteins; 3) At the molecular level, KCP10043F inhibited the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (p70S6K) pathway and activated the c-Jun N-terminal kinase (JNK)/c-Jun pathway; 4) KCP10043F mediated the Ca2+/Calcium-calmodulin-dependent kinase II (CaMKII) pathway by inducing endoplasmic reticulum (ER) stress; 5) α-Tocopherol controlled KCP10043F-induced cell cycle arrest and apoptosis by attenuating ER stress. These results demonstrate the potential of KCP10043F as a therapeutic candidate for human pancreatic cancer.

Keywords:  Apoptosis; Cell cycle arrest; ER stress; KCP10043F; Pancreatic cancer; T-type calcium channel blocker

DOI:  https://doi.org/10.1016/j.lfs.2025.123983