bims-unfpre 2026-05-24 papers

Issue of 2026–05–24
six papers selected by
Susan Logue, University of Manitoba

Neurochem Res. 2026 May 18. pii: 158. [Epub ahead of print]51(3):

Unfolded Protein Response in Glioblastoma: Mechanisms of Proteostasis, Tumor Adaptation, and Therapeutic Relevance.

Glioblastoma (GBM) is an aggressive brain tumor that rapidly develops resistance to standard clinical therapies. The tumor microenvironment of GBM is highly hostile, characterized by hypoxia, elevated reactive oxygen species, and severe metabolic stress. These conditions promote protein misfolding, particularly in the endoplasmic reticulum (ER), thereby triggering ER stress. The unfolded protein response (UPR) is an adaptive signaling pathway that mitigates ER stress, restores proteostasis, and promotes cellular survival. Activation of UPR signaling provides a survival advantage to GBM cells under these adverse conditions. This signaling is closely associated with drug resistance and malignant progression in GBM. Furthermore, inhibition of UPR sensors exhibits anticancer effects, highlighting their potential as therapeutic targets in GBM. This review describes the biological functions of UPR sensors and their roles in GBM pathogenesis and treatment response.

Keywords: ATF6; Endoplasmic reticulum stress; Glioblastoma; IRE1; PERK; Unfolded protein response

DOI: https://doi.org/10.1007/s11064-026-04772-0

Apoptosis. 2026 05 18. pii: 145. [Epub ahead of print]31(6):

The GPX1-OSBPL8 axis: integrating ER ferroptosis and apoptotic signaling.

Renin Chang, Chen-Yueh Wen, Su-Boon Yong, Chia-Jung Li.

The classification of regulated cell death (RCD) has evolved from discrete, siloed pathways into an integrated network of metabolic and proteostatic checkpoints. For over a decade, the glutathione peroxidase 4 (GPX4)-dependent neutralization of lipid hydroperoxides on the plasma membrane was considered the primary defense against ferroptosis. However, the landmark discovery by Xia et al. [1] in Cell has identified a "non-canonical" ferroptosis pathway governed by the GPX1-OSBPL8 axis, which operates specifically at the endoplasmic reticulum (ER). By elucidating how the lipid transfer protein OSBPL8 recruits GPX1 to reduce peroxidized phosphatidic acid (PA-OOH), this research provides a definitive organelle-specific mechanism for lipid-driven cell death. For the field of apoptosis, this discovery is pivotal: it positions the ER as a central decision-making hub where ferroptotic lipid damage converges with intrinsic apoptotic signals via ER stress, the Unfolded Protein Response (UPR), and unregulated calcium dynamics. This commentary evaluates the mechanistic underpinnings of this non-canonical axis and explores the synergistic potential of targeting ER-localized death programs in oncology.

DOI: https://doi.org/10.1007/s10495-026-02355-6

bioRxiv. 2026 May 07. pii: 2026.05.03.720925. [Epub ahead of print]

Stress-Responsive Protein IFRD1 Protects Assembled Ribosomes via a Ribosome-Salvaging Mechanism.

Charles J Cho, Molly K Crowder, Amala K Rougeau, Thanh Nguyen, Steven J Bark, Sammy Lee, Jeffrey W Brown, Jason C Mills.

The ability of epithelial cells to cope with injury and undergo regeneration depends on tightly coordinated cellular responses. IFRD1 is a stress-responsive protein that is evolutionarily conserved and required for the cellular regeneration program paligenosis; however, how IFRD1 works in paligenosis is not known. Here we demonstrate that IFRD1 is primarily a cytosolic ribosome-binding protein, specifically binding 80S monosomes that are not actively engaged in translation. Using multiple in vivo and in vitro injury models, including cerulein-induced pancreatitis in mice and tunicamycin-induced ER stress in cell culture, we demonstrate that IFRD1 acts as a ribosome-salvaging factor, preventing ribosomes from degradation. In the absence of IFRD1 during ER stress, non-translating 80S ribosomes were unstable and prone to disassembly and selective degradation. The resulting accumulation of degraded ribosomal subunits overwhelmed cellular autophagic machinery, as evidenced by accumulation of the autophagy-tagging protein p62, even though overall autophagic flux remained unaffected. Ultimately, cells lacking IFRD1 showed reduced mTORC1 activity followed by increased cell death, consistent with patterns observed in cells lacking IFRD1 during paligenosis. Thus, we detail a previously unrecognized cellular function for IFRD1 in stabilizing and preserving the mature ribosome pool during metabolic and translational transitions such as paligenosis.

DOI: https://doi.org/10.64898/2026.05.03.720925

Proc Natl Acad Sci U S A. 2026 May 26. 123(21): e2519235123

OptoRibo-seq for spatiotemporally resolved mapping of the local protein translatome.

Ruixuan Wang, Ruixiang Wang, Wentao Wang, Yanjun Liu, Fu Zheng, Huixin Luo, Peng R Chen, Peng Zou.

Localized protein translation occurs in numerous subcellular compartments and regulates diverse biological processes by rapidly changing protein compositions in response to subcellular needs. Existing assays for subcellular local translation either require physical isolation, which is prone to contamination and loss of material, or imaging-based readout, which is often hampered with low throughput. In this study, we report the development of the optoRibo-seq method that features photoactivatable enzyme-mediated proximity labeling of ribosomes in genetically specified subcellular locations. We demonstrate the spatial specificity of optoRibo-seq at the endoplasmic reticulum (ER) membrane, with a temporal resolution of 1 min. In cells undergoing chemically induced ER stress, optoRibo-seq allowed mapping of the dynamic changes in the ER-proximal translatome, identifying transcripts involved in protein folding and targeting. Our strategy provides a general platform for spatiotemporally resolved profiling of subcellular protein translation.

Keywords: ER stress; biotin ligase; genetic codon expansion; proximity labeling; ribosome profiling

DOI: https://doi.org/10.1073/pnas.2519235123

Cell Death Dis. 2026 May 22.

Carvedilol triggers ferroptosis in hepatic stellate cells via the ATF4/SAT1 axis promoting spermidine depletion to ameliorate liver fibrosis.

Yifu Xia, Sining Wang, Junyuan Zhu, Yuwen Chen, Xu Liu, Chunqing Zhang.

Liver fibrosis is a major pathological consequence of chronic liver injury, and carvedilol, a drug effective in reducing portal hypertension, has been shown to exert anti-fibrotic effects in recent studies, yet the precise molecular mechanism underlying this activity remains elusive. This study aimed to investigate the core scientific question of whether carvedilol alleviates liver fibrosis by inducing ferroptosis in hepatic stellate cells (HSCs) and to clarify the corresponding regulatory mechanisms. Using a CCl4-induced mouse liver fibrosis model and human (LX-2)/rat (HSC-T6) HSC lines treated with carvedilol, mechanistic analyses were conducted via Western blot, quantitative real-time PCR (RT-qPCR), RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP), as well as functional assays involving genetic manipulation and pharmacological inhibitors. Carvedilol significantly attenuated HSCs activation and ameliorated liver fibrosis in mice, and it induced ferroptosis in HSCs-characterized by mitochondrial shrinkage, lipid peroxidation, and iron accumulation-an effect that was abrogated by the ferroptosis inhibitor ferrostatin-1. Mechanistically, carvedilol triggered endoplasmic reticulum (ER) stress to activate the PERK/eIF2α/ATF4 signaling axis, and ATF4 transcriptionally upregulated spermidine/spermine N1-acetyltransferase 1 (SAT1). Ectopic overexpression of SAT1 alone was sufficient to induce ferroptosis and suppress HSCs activation, whereas SAT1 knockdown completely abolished the aforementioned effects of carvedilol. Importantly, SAT1 catalyzed spermidine depletion, which led to the post-transcriptional downregulation of GPX4 and xCT proteins, and exogenous spermidine supplementation effectively rescued SAT1-overexpression-induced ferroptosis in HSCs. Collectively, our findings demonstrate that carvedilol ameliorates liver fibrosis by inducing HSCs ferroptosis via the ER stress/ATF4/SAT1/spermidine depletion axis. This study identifies a novel regulatory role of spermidine metabolism in HSCs ferroptosis and liver fibrogenesis, and further establishes spermidine metabolism as a potential and specific therapeutic target for fibrotic liver diseases.

DOI: https://doi.org/10.1038/s41419-026-08898-5

Cell Death Dis. 2026 May 22.

Mitochondria-targeted metformin analogs activate the ER stress-unfolded protein response pathway to drive apoptosis in pancreatic cancer.

Maria Poimenidou, Jordan M Bobek, Donovan Drouillard, Tyler Harris, Elisabeth Solis, Chad Darnell, Donna McAllister, Robert F Keyes, Mayumi Ishihara-Aoki, Kazuhiro Aoki, Daisy Sahoo, Balaraman Kalyanaraman, Brian C Smith, Michael B Dwinell.

Accumulating evidence indicates that evasion of apoptosis and metabolic reprogramming are necessary for pancreatic cancer growth, early invasion, and chemotherapeutic resistance. Building on our prior work, we investigated the anti-tumor potential of a rationally designed mitochondria-targeted variant of the anti-diabetic drug metformin, Mito-Met10, in cell culture models and orthotopic xenografts. Using MALDI-mass spectrometry imaging, therapeutic concentrations of fluorinated Mito-Met10 were shown to preferentially localize within pancreatic tumors relative to adjacent tissue and liver. Treatment suppressed tumor growth, reduced tumor weights, and increased apoptosis in vivo. Murine and human pancreatic cancer cells demonstrated potent anti-proliferative activity, with low micromolar IC50 values, and a concomitant induction of apoptotic programmed cell death in vitro. Seahorse metabolic flux analysis revealed reduced basal and ATP-linked mitochondrial respiration following Mito-Met10 treatment without a compensatory increase in glycolysis. Unbiased bulk RNA sequencing revealed significant enrichment of endoplasmic reticulum stress and unfolded protein response pathways, validated by qPCR across pancreatic cancer models, with broad upregulation of UPR-associated genes, establishing that Mito-Met10 activation of this stress response is conserved. Mito-Met10 caused extensive cytoplasmic vacuolization, mitochondrial swelling, and loss of mitochondrial membrane potential, indicative of severe organelle damage. Mito-Met10 activated PERK-eIF2α-ATF4-CHOP signaling, including upregulation of ATF4 and downstream pro-apoptotic transcriptional programs. Pharmacologic inhibition of ISR abrogated apoptotic signaling, demonstrating that PERK-eIF2α-ATF4-CHOP-mediated ISR activation functionally contributes to the anti-tumor effects of Mito-Met10. Consistent with these findings, orthotopic tumors from Mito-Met10-treated mice exhibited increased nuclear ATF4 staining compared with vehicle controls. Collectively, this study links mitochondrial stress to ER stress-associated apoptosis and identifies mitochondrial stress as a tractable vulnerability that can be manipulated to positively engage anti-tumor responses in pancreatic cancer.

DOI: https://doi.org/10.1038/s41419-026-08859-y