bims-unfpre 2025-04-20 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–04–20
ten papers selected by
Susan Logue, University of Manitoba

Endoplasmic Reticulum Stress in Acute Myeloid Leukemia: Pathogenesis, Prognostic Implications, and Therapeutic Strategies.
The PERK-eIF2α-ATF4 Axis Is Involved in Mediating ER-Stress-Induced Ferroptosis via DDIT4-mTORC1 Inhibition and Acetaminophen-Induced Hepatotoxicity.
The unfolded protein response is a potential therapeutic target in pathogenic fungi.
Unveiling the impact of ERAP1 and ERAP2 on migration, angiogenesis and ER stress response.
Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice.
Autophagy, ER-phagy and ER dynamics during cell differentiation.
ATF6α inhibits ΔNp63α expression to promote breast cancer metastasis by the GRP78-AKT1-FOXO3a signaling.
Identification of a Selective Pharmacologic IRE1/XBP1s Activator with Enhanced Tissue Exposure.
Targeting ATF6α Attenuates UVB-Induced Senescence and Improves Skin Homeostasis by Regulating IL8 Expression.
The mitochondrial unfolded protein response: acting near and far.

Int J Mol Sci. 2025 Mar 27. pii: 3092. [Epub ahead of print]26(7):

Endoplasmic Reticulum Stress in Acute Myeloid Leukemia: Pathogenesis, Prognostic Implications, and Therapeutic Strategies.

Wojciech Wiese, Grzegorz Galita, Natalia Siwecka, Wioletta Rozpędek-Kamińska, Artur Slupianek, Ireneusz Majsterek.

  Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy that poses a significant therapeutic challenge due to its high recurrence rate and demanding treatment regimens. Increasing evidence suggests that endoplasmic reticulum (ER) stress and downstream activation of the unfolded protein response (UPR) pathway play a key role in the pathogenesis of AML. ER stress is triggered by the accumulation of misfolded or unfolded proteins within the ER. This causes activation of the UPR to restore cellular homeostasis. However, the UPR can shift from promoting survival to inducing apoptosis under prolonged or excessive stress conditions. AML cells can manipulate the UPR pathway to evade apoptosis, promoting tumor progression and resistance against various therapeutic strategies. This review provides the current knowledge on ER stress in AML and its prognostic and therapeutic implications.

Keywords:  ATF6; IRE1α; PERK; acute myeloid leukemia; endoplasmic reticulum stress; hematopoietic stem cells; unfolded protein response

DOI:  https://doi.org/10.3390/ijms26073092
Antioxidants (Basel). 2025 Mar 03. pii: 307. [Epub ahead of print]14(3):

The PERK-eIF2α-ATF4 Axis Is Involved in Mediating ER-Stress-Induced Ferroptosis via DDIT4-mTORC1 Inhibition and Acetaminophen-Induced Hepatotoxicity.

Thu-Hang Thi Nghiem, Kim Anh Nguyen, Fedho Kusuma, Soyoung Park, Jeongmin Park, Yeonsoo Joe, Jaeseok Han, Hun Taeg Chung.

  Ferroptosis, a regulated form of cell death characterized by lipid peroxidation and iron accumulation, is increasingly recognized for its role in disease pathogenesis. The unfolded protein response (UPR) has been implicated in both endoplasmic reticulum (ER) stress and ferroptosis-mediated cell fate decisions; yet, the specific mechanism remains poorly understood. In this study, we demonstrated that ER stress induced by tunicamycin and ferroptosis triggered by erastin both activate the UPR, leading to the induction of ferroptotic cell death. This cell death was mitigated by the application of chemical chaperones and a ferroptosis inhibitor. Among the three arms of the UPR, the PERK-eIF2α-ATF4 signaling axis was identified as a crucial mediator in this process. Mechanistically, the ATF4-driven induction of DDIT4 plays a pivotal role, facilitating ferroptosis via the inhibition of the mTORC1 pathway. Furthermore, acetaminophen (APAP)-induced hepatotoxicity was investigated as a model of eIF2α-ATF4-mediated ferroptosis. Our findings reveal that the inhibition of eIF2α-ATF4 or ferroptosis protects against APAP-induced liver damage, underscoring the therapeutic potential of targeting these pathways. Overall, this study not only clarifies the intricate role of the PERK-eIF2α-ATF4 axis in ER-stress-and erastin-induced ferroptosis but also extends these findings to a clinically relevant model, providing a foundation for potential therapeutic interventions in conditions characterized by dysregulated ferroptosis and ER stress.

Keywords:  DDIT4; ER stress; GPX4; PERK; ferroptosis; unfolded protein response

DOI:  https://doi.org/10.3390/antiox14030307
FEBS J. 2025 Apr 14.

The unfolded protein response is a potential therapeutic target in pathogenic fungi.

Hao Zhou, Jinping Zhang, Rong Wang, Ju Huang, Caiyan Xin, Zhangyong Song.

  Pathogenic fungal infections cause significant morbidity and mortality, particularly in immunocompromised patients. The frequent emergence of multidrug-resistant strains challenges existing antifungal therapies, driving the need to investigate novel antifungal agents that target new molecular moieties. Pathogenic fungi are subjected to various environmental stressors, including pH, temperature, and pharmacological agents, both in natural habitats and the host body. These stressors elevate the risk of misfolded or unfolded protein production within the endoplasmic reticulum (ER) which, if not promptly mitigated, can lead to the accumulation of these proteins in the ER lumen. This accumulation triggers an ER stress response, potentially jeopardizing fungal survival. The unfolded protein response (UPR) is a critical cellular defense mechanism activated by ER stress to restore the homeostasis of protein folding. In recent years, the regulatory role of the UPR in pathogenic fungi has garnered significant attention, particularly for its involvement in fungal adaptation, regulation of virulence, and drug resistance. In this review, we comparatively analyze the UPRs of fungi and mammals and examine the potential utility of the UPR as a molecular antifungal target in pathogenic fungi. By clarifying the specificity and regulatory functions of the UPR in pathogenic fungi, we highlight new avenues for identifying potential therapeutic targets for antifungal treatments.

Keywords:  cellular stress response; pathogenic fungus; regulatory function; unfolded protein response therapeutic target

DOI:  https://doi.org/10.1111/febs.70100
Front Cell Dev Biol. 2025 ;13 1564649

Unveiling the impact of ERAP1 and ERAP2 on migration, angiogenesis and ER stress response.

Irma Saulle, Alessandra Velia Vitalyos, Daniel D'Agate, Mario Clerici, Mara Biasin.

  Recent studies have investigated the key roles exerted by ERAP1 and ERAP2 in maintaining cellular homeostasis, emphasizing their functions beyond traditional antigen processing and presentation. In particular, genetic variants of these IFNγ-inducible aminopeptidases significantly impact critical cellular pathways, including migration, angiogenesis, and autophagy, which are essential in immune responses and disease processes. ERAP1's influence on endothelial cell migration and VEGF-driven angiogenesis, along with ERAP2's role in managing stress-induced autophagy via the UPR, highlights their importance in cellular adaptation to stress and disease outcomes, including autoimmune diseases, cancer progression, and infections. By presenting recent insights into ERAP1 and ERAP2 functions, this review underscores their potential as therapeutic targets in immune regulation and cellular stress-response pathways.

Keywords:  ER stress; ERAPs; autopaghy; cell biology; cell migration

DOI:  https://doi.org/10.3389/fcell.2025.1564649
Elife. 2025 Apr 17. pii: RP100581. [Epub ahead of print]13

Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice.

Dan Wu, Venkateswararao Eeda, Zahra Maria, Komal Rawal, Audrey Wang, Oana Herlea-Pana, Ram Babu Undi, Hui-Ying Lim, Weidong Wang.

  Overnutrition engenders the expansion of adipose tissue and the accumulation of immune cells, in particular, macrophages, in the adipose tissue, leading to chronic low-grade inflammation and insulin resistance. In obesity, several proinflammatory subpopulations of adipose tissue macrophages (ATMs) identified hitherto include the conventional 'M1-like' CD11C-expressing ATM and the newly discovered metabolically activated CD9-expressing ATM; however, the relationship among ATM subpopulations is unclear. The ER stress sensor inositol-requiring enzyme 1α (IRE1α) is activated in the adipocytes and immune cells under obesity. It is unknown whether targeting IRE1α is capable of reversing insulin resistance and obesity and modulating the metabolically activated ATMs. We report that pharmacological inhibition of IRE1α RNase significantly ameliorates insulin resistance and glucose intolerance in male mice with diet-induced obesity. IRE1α inhibition also increases thermogenesis and energy expenditure, and hence protects against high fat diet-induced obesity. Our study shows that the 'M1-like' CD11c+ ATMs are largely overlapping with but yet non-identical to CD9+ ATMs in obese white adipose tissue. Notably, IRE1α inhibition diminishes the accumulation of obesity-induced metabolically activated ATMs and 'M1-like' ATMs, resulting in the curtailment of adipose inflammation and ensuing reactivation of thermogenesis, without augmentation of the alternatively activated M2 macrophage population. Our findings suggest the potential of targeting IRE1α for the therapeutic treatment of insulin resistance and obesity.

Keywords:  ER stress; IRE1 alpha; adipose remodeling; adipose tissue macrophage; cell biology; insulin resistance; mouse; obesity

DOI:  https://doi.org/10.7554/eLife.100581
J Mol Biol. 2025 Apr 11. pii: S0022-2836(25)00217-7. [Epub ahead of print] 169151

Autophagy, ER-phagy and ER dynamics during cell differentiation.

Michele Cillo, Viviana Buonomo, Anna Vainshtein, Paolo Grumati.

  The endoplasmic reticulum (ER) is a multifunctional organelle essential for protein and lipid synthesis, ion transport and inter-organelle communication. It comprises a highly dynamic network of membranes that continuously reshape to support a wide range of cellular processes. During cellular differentiation, extensive remodelling of both ER architecture and its proteome is required to accommodate alterations in cell morphology and function. Autophagy, and ER-phagy in particular, plays a pivotal role in reshaping the ER, enabling cells to meet their evolving needs and adapt to developmental cues. Despite the ER's critical role in cellular differentiation, the mechanisms responsible for regulating its dynamics are not fully understood. Emerging evidence suggests that transcriptional and post-translational regulation play a role in fine-tuning ER-phagy and the unfolded protein response (UPR). This review explores the molecular basis of autophagy and ER-phagy, highlighting their role in ER remodelling during cellular differentiation. A deeper understanding of these processes could open new avenues for targeted therapeutic approaches in conditions where ER remodelling is impaired.

Keywords:  Cell Differentiation; Development; Endoplasmic Reticulum

DOI:  https://doi.org/10.1016/j.jmb.2025.169151
Cell Death Dis. 2025 Apr 13. 16(1): 289

ATF6α inhibits ΔNp63α expression to promote breast cancer metastasis by the GRP78-AKT1-FOXO3a signaling.

Hong Wang, Xin Yang, Liyuan Deng, Xuanyu Zhou, Jin Tao, Zhiqiang Wu, Hu Chen.

Endoplasmic reticulum (ER) stress is increasingly recognized as a driver of cancer progression; however, the precise molecular mechanisms by which ER stress facilitates tumor metastasis remain incompletely understood. In this study, we demonstrate that ER stress-activated ATF6α promotes breast cancer cell migration and metastasis by downregulating the expression of ΔNp63α, a key metastasis suppressor. Mechanistically, ATF6α reduces ΔNp63α expression through GRP78, which interacts with and activates AKT1. Activated AKT1 subsequently phosphorylates FOXO3a, leading to its degradation. Since FOXO3a directly transactivates ΔNp63α expression, its degradation results in reduced ΔNp63α levels. Furthermore, pharmacological inhibition or genetic knockdown of AKT1 upregulates ΔNp63α in vitro and suppresses tumor metastasis in vivo. Clinical analyses reveal that TP63 and FOXO3a expression are significantly reduced in breast cancer tissues compared to normal tissues, whereas ATF6 and GRP78 expression are elevated. Moreover, low TP63 and high GRP78 expression are associated with a poor prognosis in breast cancer patients. Collectively, these findings elucidate the pivotal role of the ATF6α-GRP78-AKT1-FOXO3a axis in chronic ER stress-mediated downregulation of ΔNp63α, establishing a molecular framework for targeting this pathway as a potential therapeutic strategy against breast cancer metastasis.

DOI: https://doi.org/10.1038/s41419-025-07619-8
ACS Chem Biol. 2025 Apr 15.

Identification of a Selective Pharmacologic IRE1/XBP1s Activator with Enhanced Tissue Exposure.

Jie Sun, Kyunga Lee, Sergei Kutseikin, Adrian Guerrero, Bibiana Rius, Aparajita Madhavan, Chavin Buasakdi, Ka-Neng Cheong, Priyadarshini Chatterjee, Dorian A Rosen, Leonard Yoon, Maziar S Ardejani, Alejandra Mendoza, Jessica D Rosarda, Enrique Saez, Jeffery W Kelly, R Luke Wiseman.

Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) has emerged as a promising strategy to mitigate etiologically diverse diseases. Despite this promise, few compounds are available to selectively activate IRE1/XBP1s signaling to probe the biologic and therapeutic implications of this pathway in human disease. Recently, we identified the compound IXA4 as a highly selective activator of protective IRE1/XBP1s signaling. While IXA4 has proven useful for increasing IRE1/XBP1s signaling in cultured cells and mouse liver, the utility of this compound is restricted by its limited activity in other tissues. To broaden our ability to pharmacologically interrogate the impact of IRE1/XBP1s signaling in vivo, we sought to identify IRE1/XBP1s activators with greater tissue activity than IXA4. We reanalyzed 'hits' from the high throughput screen used to identify IXA4, selecting compounds from structural classes not previously pursued. We then performed global RNAseq to confirm that these compounds showed transcriptome-wide selectivity for IRE1/XBP1s activation. Functional profiling revealed compound IXA62 as a selective IRE1/XBP1s activator that reduced Aβ secretion from CHO7PA2 cells and enhanced glucose-stimulated insulin secretion from rat insulinoma cells, mimicking the effects of IXA4 in these assays. IXA62 robustly and selectively activated IRE1/XBP1s signaling in the liver of mice dosed compound intraperitoneally or orally. In treated mice, IXA62 showed broader tissue activity, relative to IXA4, inducing expression of IRE1/XBP1s target genes in additional tissues such as kidney and lung. Collectively, our results designate IXA62 as a selective IRE1/XBP1s signaling activating compound with enhanced tissue activity, which increases our ability to pharmacologically probe the biologic significance and potential therapeutic utility of enhancing adaptive IRE1/XBP1s signaling in vivo.

DOI: https://doi.org/10.1021/acschembio.4c00867
Aging Cell. 2025 Apr 16. e70024

Targeting ATF6α Attenuates UVB-Induced Senescence and Improves Skin Homeostasis by Regulating IL8 Expression.

Joëlle Giroud, Pauline Delvaux, Laura Carlier, Clémentine De Schutter, Nathalie Martin, Raphaël Rouget, Ayeh Bolouki, Valérie De Glas, Inès Bouriez, Florent Bourdoux, Sophie Burteau, Julien Théry, Gauthier Decanter, Nicolas Penel, Yvan de Launoit, Benjamin Ledoux, Corinne Abbadie, Yves Poumay, Olivier Pluquet, Florence Debacq-Chainiaux.

  Skin aging is influenced by both intrinsic and extrinsic factors, particularly UV radiation, and is characterized by an accumulation of senescent cells. Remarkably, exposure to UV can trigger senescence in different skin cell types, including dermal fibroblasts. However, the molecular mechanisms underlying UV-induced senescence and the impact of the related senescence-associated secretory phenotype (SASP) on the homeostasis of the overlying epidermis remain poorly understood. Here, we identified that both chronological aging and photoaging induce the unfolded protein response (UPR) in human dermal samples. We demonstrated that silencing ATF6α disrupts the establishment of the UVB-induced senescent phenotype by preventing the onset of several senescent biomarkers and alters the composition of the SASP, consequently affecting its impact on the increased proliferation of keratinocytes embedded in reconstructed human epidermis. Moreover, we found that ATF6α partially mediates IL8 expression involved in the hyperproliferation of cultured keratinocytes. Together, our findings highlight the importance of the ATF6α/IL8 axis in regulating the homeostasis of neighboring cells during skin photoaging, thus suggesting ATF6α as a potentially promising target for senotherapeutic interventions.

Keywords:  ATF6α; UPR; UVB‐induced senescence; normal human dermal fibroblasts; skin

DOI:  https://doi.org/10.1111/acel.70024
Biol Chem. 2025 Apr 17.

The mitochondrial unfolded protein response: acting near and far.

Nikolaos Charmpilas, Qiaochu Li, Thorsten Hoppe.

  Mitochondria are central hubs of cellular metabolism and their dysfunction has been implicated in a variety of human pathologies and the onset of aging. To ensure proper mitochondrial function under misfolding stress, a retrograde mitochondrial signaling pathway known as UPRmt is activated. The UPRmt ensures that mitochondrial stress is communicated to the nucleus, where gene expression for several mitochondrial proteases and chaperones is induced, forming a protective mechanism to restore mitochondrial proteostasis and function. Importantly, the UPRmt not only acts within cells, but also exhibits a conserved cell-nonautonomous activation across species, where mitochondrial stress in a defined tissue triggers a systemic response that affects distant organs. Here, we summarize the molecular basis of the UPRmt in the invertebrate model organism Caenorhabditis elegans and in mammals. We also describe recent findings on cell-nonautonomous activation of the UPRmt in worms, flies and mice, and how UPRmt activation in specific tissues affects organismal metabolism and longevity.

Keywords:  cell-nonautonomous regulation; integrated stress response; mitochondria; mitochondrial unfolded protein response; stress signaling

DOI:  https://doi.org/10.1515/hsz-2025-0107