bims-unfpre 2026-03-29 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–03–29
eight papers selected by
Susan Logue, University of Manitoba

Allergic Inflammation Triggers the Unfolded Protein Response and Ormdl3 Expression in Rat Adipocytes, While miR-665 Inhibition Selectively Modulates the IRE1/XBP1 Pathway and IL-6 Secretion.
A GasPak-Based Ischemia Model for Studying ER Stress-Ischemia Interactions in Human Endothelial Cells.
PRAS40 activates the IRE1α-XBP-1-mediated unfolded protein response to exacerbate colorectal cancer by enhancing ST6Gal1-dependent α-2, 6 sialylation of GRP78.
Age-dependent induction of ER stress in retinal pigment epithelium impairs phagocytosis via ADAM17-dependent MERTK shedding.
Synergistic Induction of Oxidative and Endoplasmic Reticulum Stress by Tempol and ML210 Combination Therapy in B16F10 Melanoma Cells.
Heat shock factor-1 alleviates ER-stress in Caenorhabditis elegans.
UPR/ATF4/Noxa pathway overactivation through SERCA2 inhibition or ONC201 treatment combined with ABT-737 triggers apoptosis in chemoresistant ovarian cancer cells and patient-derived tumor organoids.
Noncanonical role of KDM5C in conferring bortezomib resistance via the PERK‒Nrf2 axis in multiple myeloma.

Int J Mol Sci. 2026 Mar 12. pii: 2608. [Epub ahead of print]27(6):

Allergic Inflammation Triggers the Unfolded Protein Response and Ormdl3 Expression in Rat Adipocytes, While miR-665 Inhibition Selectively Modulates the IRE1/XBP1 Pathway and IL-6 Secretion.

Joanna Nowakowska-Lewicka, Wojciech Langwiński, Tatiana Wojciechowicz, Marek Skrzypski, Beata Narożna, Maria Kachel, Kosma Sakrajda, Zuzanna Stachowiak, Aleksandra Szczepankiewicz.

  Endoplasmatic reticulum (ER) stress is an imbalance between the load of unfolded proteins and the ability of cellular mechanisms to handle it. Under the influence of this stress, cells activate the unfolded protein response (UPR). The molecular mechanisms of ER stress have been repeatedly linked to metabolic and inflammatory diseases, such as obesity and allergic inflammation. The aim of our study was to investigate if the allergic inflammation in adipocytes affects the expression of UPR pathway genes and Ormdl3 and whether miRNA-665 can modify inflammatory response in adipocytes. We isolated rat preadipocytes and treated them with IL-13 to induce allergic inflammation. Later, we transfected them with miRNA-665 inhibitor. RNA was isolated from adipocytes and analyzed by qPCR. From cell culture medium, we performed an LDH assay and ELISA for secreted IL-6 and TNFα proteins. A comparison between control cells and IL-13-treated cells showed significant differences in the expression of most of the studied UPR pathway genes, Ormdl3 and Bax. Comparing the IL-13-treated cells after miR-665 transfection with non-transfected ones, we observe significant differences only in Ire1α gene. Our research suggests that allergic inflammation induces an adaptive UPR in adipocytes and miR-665 may selectively modify this response, triggering the IRE1/XBP1 axis.

Keywords:  ER stress; UPR; adipocytes; allergic inflammation; miR-665; miRNA

DOI:  https://doi.org/10.3390/ijms27062608
Methods Protoc. 2026 Mar 04. pii: 39. [Epub ahead of print]9(2):

A GasPak-Based Ischemia Model for Studying ER Stress-Ischemia Interactions in Human Endothelial Cells.

Mathilde Hoareau, Grégorie Lebeau, Luce Muzi, Jérémy Fontaine, Pascale Krejbich-Trotot, Olivier Meilhac, Christine Robert-Da Silva, Wildriss Viranaicken.

  During ischemia, endothelial cell integrity is compromised, as a consequence, blood barrier homeostasis is disrupted. Therefore, the structural and functional preservation of endothelial cells is paramount when trying to improve outcomes after ischemic injury. Endoplasmic reticulum (ER) stress is increasingly recognized as a key player in ischemic injury through unfolded protein response (UPR) signalling, and its crosstalk with mitochondrial death pathways. This study provides a cost-effective and straightforward method to delve into the relationship between ER stress and ischemia in human microvascular endothelial cells-1 (HMEC-1). HMEC-1 was exposed to 8 h of oxygen-glucose deprivation (OGD) in glucose-free medium with rapidly induced hypoxia. Hypoxia, oxygen consumption, cell viability, apoptosis, and ER stress markers (BiP/GRP78, PERK, ATF6, IRE1/XBP1s, CHOP) were assessed by RT-qPCR and Western blot. Cell viability decreased by approximately 33% following OGD, while CHOP expression increased ~4-fold, indicating significant ER stress induction. The model enables quantification of metabolic stress (OCR), as well as evaluation of viability loss, membrane integrity, apoptotic commitment, and discrimination between ER stress resolution versus maladaptation. Overall, GasPak EZ Pouch Systems provide a reproducible and practical in vitro platform to study ischemic injury down to the mechanistic details of ER-mitochondria signalling. They give the opportunity to evaluate therapeutic approaches that target ER homeostasis to limit apoptosis and/or recovery of metabolic function after ischemia. This method could allow rapid screening of ER stress-modulating interventions aimed at preserving endothelial barrier function, in various ischemic contexts.

Keywords:  ER stress; apoptosis; endothelial cell; ischemia; oxygen deprivation

DOI:  https://doi.org/10.3390/mps9020039
Neoplasia. 2026 Mar 21. pii: S1476-5586(26)00026-6. [Epub ahead of print]75 101297

PRAS40 activates the IRE1α-XBP-1-mediated unfolded protein response to exacerbate colorectal cancer by enhancing ST6Gal1-dependent α-2, 6 sialylation of GRP78.

Hongming Teng, Yuxin Guo, Xinran Chen, Anlian Fan, Chengfei Zhang, Ting Zhang, Yuanyuan Luo, Lin Huang.

  Colorectal cancer (CRC) progression could be fueled by the activation of the unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress. The proline-rich Akt1 substrate of 40 kDa (PRAS40) is implicated in cancer progression, but its role in the UPR remains unclear. Herein, we demonstrate that PRAS40 promotes the inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) axis-dependent UPR in driving CRC progression. Mechanistically, PRAS40 interacts with ER chaperone glucose-regulated protein 78 (GRP78) and enhances its N-glycosylation. Moreover, PRAS40 improves the interaction between GRP78 and ST6 β-galactoside α-2, 6-sialyltransferase 1 (ST6Gal1), leading to increased α-2, 6-sialylation of GRP78 and the UPR triggered by ER stress. Furthermore, we identified the natural compound β-sitosterol as a novel ST6Gal1 inhibitor, which attenuated PRAS40-triggered tumor growth. Collectively, these findings unveil a PRAS40-ST6Gal1-GRP78 axis that drives CRC progression through activating the IRE1α-XBP-1-mediated UPR and nominate ST6Gal1 as a promising therapeutic target.

Keywords:  Colorectal cancer; Endoplasmic reticulum stress; GRP78; PRAS40; The unfolded protein response

DOI:  https://doi.org/10.1016/j.neo.2026.101297
J Biol Chem. 2026 Mar 23. pii: S0021-9258(26)00267-X. [Epub ahead of print] 111397

Age-dependent induction of ER stress in retinal pigment epithelium impairs phagocytosis via ADAM17-dependent MERTK shedding.

Hiroto Yasuda, Shinsuke Nakamura, Aimi Shirakawa, Yoshiki Kuse, Kazutoshi Mori, Masamitsu Shimazawa.

  Retinal pigment epithelium (RPE) plays a crucial role in maintaining visual function by phagocytosing photoreceptor outer segments (POS). Age-related decline in RPE phagocytic activity has been linked to the development of degenerative retinal diseases, including age-related macular degeneration (AMD). However, the underlying mechanisms of RPE phagocytic dysfunction remain poorly understood. In this study, we examined age-related induction of endoplasmic reticulum (ER) stress in RPE cells and its association with POS phagocytosis using tissues from middle-aged mice and cultured RPE cells. In the RPE-choroid complex of 12-month-old mice, ER stress marker proteins were significantly upregulated compared to younger mice. Notably, this increase was absent in the neural retina at the same age. In cultured RPE cells, pharmacological induction of ER stress by tunicamycin (Tm) significantly reduced both phagocytic activity and lysosomal function. Treatment with sodium 4-phenylbutyrate, a chemical chaperone, and transfection with chaperone protein-inducible plasmids alleviated the ER stress-induced phagocytic dysfunction in RPE cells. In the lysates of ER stress-induced RPE cells, the extracellular domain of Mer tyrosine kinase receptor (MERTK) and phosphorylation of focal adhesion kinase were significantly decreased. Mechanistically, ER stress promoted the maturation of a disintegrin and metalloprotease 17 (ADAM17) through Ca2+-dependent activation of the Furin protease, leading to MERTK shedding. Furthermore, ADAM17 knockdown attenuated the Tm-induced impairment of POS internalization. Collectively, our findings suggest that ER stress impairs RPE phagocytosis through an integrated mechanism and may contribute to the pathogenesis of AMD.

Keywords:  ADAM; aging; calcium intracellular release; endoplasmic reticulum stress (ER stress); eye; phagocytosis; retina

DOI:  https://doi.org/10.1016/j.jbc.2026.111397
Int J Mol Sci. 2026 Mar 14. pii: 2675. [Epub ahead of print]27(6):

Synergistic Induction of Oxidative and Endoplasmic Reticulum Stress by Tempol and ML210 Combination Therapy in B16F10 Melanoma Cells.

Ebru Çelik, Percin Pazarci, Ömer Kokaçya, Halil Mahir Kaplan.

  Given the challenges in treating metastatic melanomas, there is a growing need for novel and effective therapeutic strategies. This study aimed to understand molecular mechanisms underlying synergistic effects of a Tempol and ML210 combination in B16F10 murine melanoma cells and to evaluate its therapeutic potential. We hypothesized that this combination would synergistically induce cell death by increasing oxidative stress and triggering ER stress. B16F10 melanoma cells were treated with Tempol and ML210 alone or in combination for 48 h. Cell viability was determined using MTT assay. Oxidative stress was evaluated by measuring Total Antioxidant Status (TAS), Total Oxidant Status (TOS), and intracellular H2O2 levels. Apoptotic markers (caspase-3, Bax, Bcl-2) and ER stress proteins (GRP78, GADD153, IRE1α, ATF6) were quantified by ELISA. Combination treatment significantly inhibited cell proliferation compared to monotherapies. Molecular analyses revealed that combination caused depletion of TAS and increase in TOS and intracellular H2O2 levels. Furthermore, combination treatment synergistically upregulated ER stress markers and pro-apoptotic proteins while significantly suppressing anti-apoptotic Bcl-2 expression. In conclusion, the combination of Tempol and ML210 synergistically induces cell death in B16F10 melanoma cells by disrupting redox balance and activating ER stress-mediated apoptosis. These findings suggest a potential strategy for melanoma treatment that warrants further in vivo investigation.

Keywords:  ER stress; ML210; Tempol; ferroptosis; melanoma; oxidative stress

DOI:  https://doi.org/10.3390/ijms27062675
Sci Rep. 2026 Mar 25. pii: 9928. [Epub ahead of print]16(1):

Heat shock factor-1 alleviates ER-stress in Caenorhabditis elegans.

Saqib Ahmed, Dániel Kovács, Márton Kovács, Mónika Kosztelnik, Bernadette Hotzi, Tímea Sigmond, Éva Saskői, Viktor Vázsony Vincze, Viktor Erdélyi, Veronika Deák, Ibolya Stiller, Tibor Vellai, János Barna.

  Cells can be exposed to many different stimuli that induce a variety of stresses, such as oxidative stress and proteotoxic stress of the cytoplasm, endoplasmic reticulum or mitochondria. These types of stresses trigger conserved molecular pathways (e.g., heat shock response, unfolded protein response, and autophagy) that can restore cellular homeostasis. Dysfunction (deficiency or hyperactivity) of these pathways is associated with aging and pathologies such as neurodegenerative diseases, diabetes and cancer. The basic molecular machinery of these stress response pathways has been elucidated, but how these pathways interact remains a vibrant area of research. Here, we show that the heat shock transcription factor-1 (HSF-1), the master regulator of the heat shock response, is required for efficient activation of the endoplasmic reticulum unfolded protein response (UPRER) in the nematode Caenorhabditis elegans. Tolerance against tunicamycin-induced ER stress also requires HSF-1 activity. We found that mRNA levels of several genes involved in the UPRER are regulated by HSF1 in human cell lines. These results suggest that HSF-1 plays a critical role in the cellular response to ER stress.

Keywords:   Caenorhabditis elegans ; Endoplasmic reticulum; Heat shock factor; Proteotoxic stress; Unfolded protein response

DOI:  https://doi.org/10.1038/s41598-026-43060-3
Cell Death Dis. 2026 Mar 27.

UPR/ATF4/Noxa pathway overactivation through SERCA2 inhibition or ONC201 treatment combined with ABT-737 triggers apoptosis in chemoresistant ovarian cancer cells and patient-derived tumor organoids.

Sahra Messaoudi, Romane Florent, Louis-Bastien Weiswald, Guillaume Desmartin, Lucie Lecouflet, Steven Lohard, Léa Grunchec, Edwige Abeilard, Marilyne Guillamin, Jordane Divoux, Benoît Goudergues, Emilie Brotin, Enora Dolivet, Laurent Poulain, Monique N'Diaye.

Ovarian cancer has a poor clinical prognosis due to chemoresistance following carboplatin/paclitaxel treatment. This phenomenon can be explained by an imbalanced ratio of [anti-apoptotic (BCL-xL/MCL-1)] to [pro-apoptotic (Noxa, BIM, PUMA)] BCL-2 family members that prevents apoptosis initiation. Consequently, any treatment capable of counterbalancing this ratio could be beneficial in the management of ovarian cancer. Calcium signaling is strongly implicated in resistance to apoptosis, as it depends on, but also regulates, the expression of the ratio of BCL-2 family members, making calcium-targeted strategies relevant to overcoming chemoresistance. Knowing that SERCA2 calcium pumps regulation plays a major role in controlling the ER stress-induced UPR response that could lead to pro-apoptotic protein upregulation and cell death, we therefore evaluated whether their inhibition could elicit apoptosis or sensitize ovarian cancer cells to other therapeutic strategies. For this purpose, the platinum-resistant cell line, OAW42-R, was treated with anti-SERCA2 strategies which revert the BCL-2 family member expression ratio in favor of pro-apoptotic proteins. Combination with the BH3-mimetic ABT-737 exacerbates this imbalance not only by inhibiting BCL-xL activity but also through over-induction of the UPR/ATF4/Noxa axis, leading to MCL-1 inhibition. This dual effect of ABT-737 upon ER stress fully suppresses the anti-apoptotic capacities of cancer cells, leading to massive mitochondrial apoptosis. This point was supported with ONC201, the first member of the imipridone family of anticancer drugs to enter the clinic, whose ability to trigger UPR/ATF4/Noxa led to apoptosis commitment when it was combined with ABT-737 treatment. The therapeutic efficacy of these combinations was also proved in patient-derived tumor organoid models (PDTO), leading to their structural disintegration and reduced viability. Collectively, our study highlights that ABT-737, through BCL-xL inhibition and synergy with ER stress inducers, triggers ovarian cancer death, offering promising strategies for overcoming chemoresistance in relapsed ovarian cancer.

DOI: https://doi.org/10.1038/s41419-026-08559-7
Cell Death Dis. 2026 Mar 23.

Noncanonical role of KDM5C in conferring bortezomib resistance via the PERK‒Nrf2 axis in multiple myeloma.

Peifen Lu, Wenbin Shangguan, Weiwei Qian, Dongliang Wu, Wenyang Li, Jingjing Huang, Peipei Xu, Dijun Chen, Feng Li, Bing Chen, Quan Zhao.

Conventionally, KDM5C functions as a specific demethylase that targets histone H3 lysine 4 dimethyl and trimethyl modifications, crucial for gene expression. However, the role of KDM5C in multiple myeloma (MM) progression and bortezomib (BTZ) resistance has remained elusive. In this study, we found noncanonical functions of KDM5C in MM. Specifically, KDM5C binds to CBP and MYC, conferring BTZ resistance in MM through a demethylase-independent mechanism. Our investigations revealed that KDM5C is markedly upregulated in BTZ-resistant MM patients as well as those with relapsed MM. Significantly, the expression level of KDM5C exhibits an inverse correlation with the overall survival of MM patients. Moreover, KDM5C is indispensable for MM cell proliferation. Depletion of KDM5C augmented the sensitivity of MM cells to BTZ treatment both in vitro and in vivo. We found that KDM5C forms a novel complex with CBP and MYC via its PHD2 domain. This complex formation triggers lysine 27 acetylation in histone H3 (H3K27ac) and subsequent enrichment of H3K27ac on the PERK promoter. As a result, PERK transcription is activated, and Nrf2 phosphorylation is promoted, bolstering the unfolded protein response within the endoplasmic reticulum of MM cells. In contrast, the methylation status of histone H3 lysine 4 (H3K4me1/3) on the PERK promoter remains unaltered, regardless of the complex state. Taken together, the findings of this study underscore the key role of KDM5C as a driving force behind MM progression and BTZ resistance, indicating that KDM5C represents a novel and promising therapeutic target for the treatment of BTZ-resistant MM.

DOI: https://doi.org/10.1038/s41419-026-08591-7