bims-unfpre 2026-10-11 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–10–11
eight papers selected by
Susan Logue, University of Manitoba

Targeting the IRE1α/XBP1 pathway in type 2 diabetes mellitus: from ER stress signaling to therapeutic opportunity.
Responses to endoplasmic reticulum stress at a glance.
The Effects of Extracellular Vesicles From Cancer Cells in Acidosis or ER Stress to Endothelial Cells: Angiogenesis and Endothelial Activation.
The unfolded protein response in precision oncology: from mechanisms to therapeutic opportunities.
Senescent tumor cell membrane-based "time engine" nanosystem amplifies endoplasmic reticulum targeting for metastasis blockade.
Translating the Crosstalk Between Unfolded Protein Response and Ferroptosis to Cancer Therapies.
The Unfolded Protein Response as a Modulator of Cancer-Immune Cell Communication in the Tumour Microenvironment.
Targeting HSPA1A with geranylgeranylacetone alleviates ADTKD-UMOD via suppression of endoplasmic reticulum stress and ferroptosis.

Mol Biol Rep. 2026 Oct 08. pii: 1688. [Epub ahead of print]53(1):

Targeting the IRE1α/XBP1 pathway in type 2 diabetes mellitus: from ER stress signaling to therapeutic opportunity.

Olabisi Tajudeen Obafemi, Ademola Olabode Ayeleso, Bidemi Emmanuel Ekundayo, Blessing Ariyo Obafemi, Olusola Bolaji Adewale, Sogolo Lucky Lebelo, Monde Ntwasa.

  To respond to protein misfolding in the endoplasmic reticulum (ER), cells trigger the unfolded protein response (UPR) to re-establish proteostasis. However, unresolved UPR results in chronic ER stress, which is critical to the development and advancement of type 2 diabetes mellitus (T2DM), a multifactorial disease whose prevalence has continued to rise. The UPR consists of three transmembrane signaling branches - protein kinase R-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 alpha (IRE1α), which collectively attempts to restore proteostasis, or trigger apoptosis if ER stress persists. Among the three, the IRE1α pathway is the most evolutionarily conserved and serves as a central regulator of UPR signaling through the splicing of X-box binding protein 1 mRNA (XBP1s). In the adaptive mode, XBP1s drives the expression of genes that expand ER capacity and alleviate cellular stress. Conversely, chronic activation of the IRE1α pathway activates the regulated IRE1-dependent decay (RIDD) process, recruits tumour necrosis factor receptor-associated factor 2/c-Jun N-terminal kinase (JNK), and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), with their attendant deleterious effects. Thus, the therapeutic utility of the IRE1α/XBP pathway depends on the duration and extent of UPR as well as tissue and cellular metabolic state. The extensive crosstalk of the pathway with metabolic and inflammatory pathways makes it an attractive therapeutic target. This review examines the role of the IRE1α/XBP1 pathway in T2DM and highlights the potential of modulating the pathway as a novel disease-modifying strategy in the context of the increasing burden of the disease.

Keywords:  Drug target; Inositol-requiring enzyme 1-alpha; X-box binding protein 1; conserved; type 2 diabetes

DOI:  https://doi.org/10.1007/s11033-026-12876-7
J Cell Sci. 2026 Oct 01. pii: jcs264817. [Epub ahead of print]139(19):

Responses to endoplasmic reticulum stress at a glance.

Eric Chevet, Céline Philippe, Tony Avril, Elodie Lafont.

  The endoplasmic reticulum (ER) is the gateway to the eukaryotic protein secretory pathway. Beyond its role in protein biogenesis, it is central to Ca2+ homeostasis and lipid biosynthesis. This organelle, which can constitute more than 50% of the cellular membranes in secretory cells, is highly plastic and must adjust to intracellular or extracellular challenges to ensure proper protein secretion. ER stress, resulting from challenges such as accumulation, misfolding or aggregation of proteins or from disrupted ER lipid composition, can deleteriously affect cell function. Thus, the ER has evolved adaptive mechanisms that lead to cellular reprogramming to adjust its capacity to handle stress, including the unfolded protein response (UPR), which engages various ER quality control systems, protein degradation pathways and ER-organelle contacts. If this succeeds, the cell survives; but if it fails, cell death mechanisms are triggered. In this Cell Science at a Glance article and the accompanying poster, we summarize current knowledge on ER stress and control of the UPR in mammalian cells, highlighting aspects that require further attention. We also discuss recent insights that must be considered to better capture the full understanding of the ability of the ER to adjust to biological variation.

Keywords:  Contact sites; Endoplasmic reticulum; Proteostasis; UPR; Unfolded protein response

DOI:  https://doi.org/10.1242/jcs.264817
Biol Cell. 2026 Oct;118(10): e70085

The Effects of Extracellular Vesicles From Cancer Cells in Acidosis or ER Stress to Endothelial Cells: Angiogenesis and Endothelial Activation.

Ana Sayuri Yamagata, Ramon H G Teles, Nicolas J Villarinho, Ana Carolina Lima Ralph, Nicolly C Dos Santos, Kevin Perera, Gisela R Terçarioli, Amanda Ikegami, Anayara Ristow, Daniel Pecoraro Demarque, Jeremy Newton, Luiz E da Silva, Edmond W K Young, Ruy G Jaeger, Vanessa Morais Freitas.

  Tumor-derived extracellular vesicles (EVs) facilitate metastatic progression by transferring bioactive cargo to recipient cells, thereby increasing endothelial permeability and promoting angiogenesis. The harsh conditions of the tumor microenvironment, such as extracellular acidosis, can alter the content of EVs, leading to changes in recipient cells, including endoplasmic reticulum (ER) stress. This study aimed to investigate whether EVs released by tumor cells adapted to acidosis or ER stress can alter endothelial functional properties. ER stress was induced in MDA-MB-231 breast cancer cells with tunicamycin, and adaptation to acidosis was achieved by culturing at pH 6.5 for 30 days. Large extracellular vesicles (LEVs) in these conditions were isolated by centrifugation. LEVs were characterized by nanoparticle tracking analysis (NTA), immunogold, Western blot, and high-performance liquid chromatography (HPLC). ER stress and autophagy markers were quantified by Western blot; cancer cells' adhesion to endothelial cells was assessed by adhesion assay; barrier permeability by dextran diffusion in an organ-on-a-chip model; migration by wound healing assay, and angiogenesis by tube formation assay. Tunicamycin was not detected in LEV from tunicamycin-treated cells (LEV T). LEV T increased the migration of endothelial cells, while not inducing ER stress, nor altering adhesion, angiogenesis, or permeability. Acidosis-adapted cells did not have greater UPR activation, but their LEVs (LEV 6.5) induced ER stress, reduced adhesion and angiogenesis, and increased permeability and migration. These findings indicate that LEVs from acidosis-adapted tumor cells reprogram endothelial physiology, supporting a potential role in metastatic progression.

Keywords:  acidosis; cancer; endoplasmic reticulum stress; endothelial cells; extracellular vesicles

DOI:  https://doi.org/10.1111/boc.70085
Trends Mol Med. 2026 Oct 06. pii: S1471-4914(26)00221-2. [Epub ahead of print]

The unfolded protein response in precision oncology: from mechanisms to therapeutic opportunities.

Quentin Bourgery, Dimitrios Doultsinos, Antoine Galmiche, Eric Chevet, Olivier Pluquet.

  The unfolded protein response (UPR) is a fundamental stress pathway coopted in cancer, and it is thought to drive adaptation, tumor progression, and therapeutic resistance. While the analysis of 'single-effector' biomarkers within the tumor microenvironment often fails to capture its spatial, temporal, and cellular complexity, recent advances in high-resolution spatial transcriptomics and single-cell multiomics may enable a shift from static readouts toward more comprehensive multigene UPR signatures. This could help resolve proteostatic heterogeneity at unprecedented resolution. In this review, we provide a pan-cancer perspective on using these quantitative signatures to map proteostatic states. By combining cell biology, mechanobiology, and computational pathology, our proposed translational framework blends morphological hallmarks with multiomic UPR signatures. Although still requiring prospective clinical validation, this approach could improve patient stratification and treatment decisions, advancing the field of precision oncology.

Keywords:  UPR; multigenic signatures; patient stratification; precision oncology; proteostasis; spatiotemporal heterogeneity

DOI:  https://doi.org/10.1016/j.molmed.2026.09.005
Sci Adv. 2026 Oct 09. 12(41): eaeh0494

Senescent tumor cell membrane-based "time engine" nanosystem amplifies endoplasmic reticulum targeting for metastasis blockade.

Jing Tao, Yuzhen Guo, Fengzhi Zhang, Jiahui Wu, Liyun Xing, Jinxia Kong, Lian Li, Zhou Zhou, Yuan Huang.

As an important component of biomimetic drug delivery systems, cell membrane-coated nanoparticles are widely used for subcellular delivery. However, the influence of cell membranes at different life cycles on subcellular delivery remains unexplored. Our previous study demonstrated that senescent tumor cell membrane-coated nanoparticles (SNP) displayed superior endoplasmic reticulum (ER) targeting efficiency in tumor cells. After inducing tumor cells into senescence, SNP showed greater accumulation in ER. Herein, we design a "time engine" nanosystem for amplified ER targeting: Firstly, ribociclib is encapsulated into SNP (R@SNP) to induce tumor cell senescence; then, SNP loaded with brefeldin A (B@SNP) is used to trigger ER stress. By sequential therapy, R@SNP disrupts the cytoskeleton of 4T1 tumor cells to eliminate ER-targeting barriers and remodels the tumor immune microenvironment; B@SNP boosts ER-targeting efficiency and triggers intense ER stress. Collectively, such time engine nanosystem achieves excellent ER accumulation and antimetastatic efficacy in 4T1 tumor-bearing mice, providing an innovative perspective for subcellular delivery and tumor treatment.

DOI: https://doi.org/10.1126/sciadv.aeh0494
Curr Oncol Rep. 2026 Oct 09. pii: 101. [Epub ahead of print]28(1):

Translating the Crosstalk Between Unfolded Protein Response and Ferroptosis to Cancer Therapies.

P M Quan Mai, Arundhati Shandilya, Sai Kumar Samala, Tam-Anh Truong, Prudhvi Chand Mallepaddi, Prapannajeet Biswal, Bhoomika Muruvekere Lakshmisha, Geraldine Vijay, Lydia Wt Cheung, Sunil Krishnan.

   PURPOSE OF REVIEW: To survive the proteotoxic and oxidative stress that are prototypical of rapidly multiplying cells, cancer cells must successfully navigate two existential threats: the danger of protein misfolding in the endoplasmic reticulum and the peril of iron-catalyzed peroxidation of membrane lipids. Over the past few decades, the cellular responses to these pressures have been studied independently. This review underscores emerging evidence coupling two erstwhile distinct cellular processes: (i) the unfolded protein response (UPR) that acts as a guardian of proteostasis and a crucial metabolic rheostat, through its three arms (IRE1α, PERK, and ATF6) and (ii) ferroptosis that leads to cell death due to iron-dependent accumulation of lethal levels of lipid peroxides.
RECENT FINDINGS: Multiple intersections between UPR and ferroptosis control the fate of cells, with a well-compensated UPR response leading to cell survival whereas an overwhelmed UPR response routing cells to ferroptosis, depending on cellular contexts such as the expression of antioxidant enzymes, the composition of membrane lipids, and the bioavailability of catalytic iron. The crosstalk has been shown to occur at different hierarchical levels, from shared upstream stress signals to convergent signaling cascades and downstream transcriptional networks. Preclinical drug-response profiles and mechanistic studies provide compelling evidence that combining UPR modulation with ferroptosis induction may represent viable cancer therapies. Investigation of the molecular determinants and context dependence of the UPR-ferroptosis axis will be critical for developing rational combination strategies toward clinical translation.

Keywords:  Combination therapy; Ferroptosis; Oxidative stress; Unfolded protein response

DOI:  https://doi.org/10.1007/s11912-026-01840-0
J Cell Mol Med. 2026 Oct;30(19): e71380

The Unfolded Protein Response as a Modulator of Cancer-Immune Cell Communication in the Tumour Microenvironment.

Yew Hwang Chee, Matthieu Moncan, Eileen Reidy, Adrienne M Gorman, Afshin Samali.

  The tumour microenvironment (TME) comprises a dynamic network of structural, cellular, and signalling components that interact to influence tumour development. Immune cells play a key role in recognizing and eliminating cancer cells through detection of tumour-derived membrane and secreted proteins processed in the endoplasmic reticulum (ER). These ER-matured proteins on target cells act as critical communication signals, coordinating immune responses against tumour cells. However, during tumorigenesis, accumulation of unfolded or misfolded proteins in the ER of the cancer cells triggers the unfolded protein response (UPR), a transcriptional program that alleviates proteotoxic stress by reshaping the cancer cell proteome and secretome, thereby promoting survival. Activation of UPR disrupts intercellular communication and ultimately impairs immune-mediated tumour clearance. Understanding this crosstalk could inform the development of therapeutics targeting UPR-driven immune modulation. This review discusses how UPR-signalling modulates tumour-immune cell interactions within the TME.

Keywords:  antigen presentation; anti‐tumour immunity; cancer therapy; endoplasmic reticulum (ER) stress; immune modulation; secretome; tumour microenvironment (TME)

DOI:  https://doi.org/10.1111/jcmm.71380
JCI Insight. 2026 Oct 06. pii: e207210. [Epub ahead of print]

Targeting HSPA1A with geranylgeranylacetone alleviates ADTKD-UMOD via suppression of endoplasmic reticulum stress and ferroptosis.

Wen Shi, Yan Yang, Xianli Wen, Qianqian Wu, Jinxuan Wei, Xin-Lu Wang, Junyuan Shen, Siqi Peng, Xiaoliang Zhang, Bi-Cheng Liu, Bin Wang.

  Missense mutations in the UMOD gene are a well-established genetic cause of autosomal dominant tubulointerstitial kidney disease (ADTKD). Here, we report two ADTKD pedigrees carrying de novo UMOD mutations, p.His36Tyr (H36Y) and p.Trp31Cys (W31C). To elucidate the underlying pathogenic mechanisms and explore targeted therapeutic strategies, we generated a UMODH36Y/+ knock-in mouse model using CRISPR/Cas9 technology, which recapitulated the major clinical manifestations observed in patients. Through single-cell RNA sequencing and experimental validation, we demonstrated that uromodulin mutations triggered endoplasmic reticulum (ER) stress and the unfolded protein response, with ferroptosis identified as the predominant mode of cell death in this disease. These findings were further confirmed in plasmid-transfected cell models expressing UMODH36Y and UMODW31C. Moreover, the molecular chaperone HSPA1A was identified as a potential therapeutic target. Geranylgeranylacetone, targeting HSPA1A as a chaperone drug, effectively mitigated endoplasmic reticulum stress, alleviated ferroptosis, and delayed the progression of renal dysfunction. Based on novel uromodulin mutations, our study reveals a pathogenic ER-ferroptosis axis in ADTKD-UMOD, deepens the insight into the pathogenesis of ADTKD-UMOD, and provides a promising strategy for developing chaperone therapy with drug repurposing in genetic kidney diseases.

Keywords:  Chaperones; Drug therapy; Genetic diseases; Genetics; Nephrology

DOI:  https://doi.org/10.1172/jci.insight.207210