bims-unfpre 2026-02-08 papers

Issue of 2026–02–08
eight papers selected by
Susan Logue, University of Manitoba

Nature. 2026 Feb 04.

Activated ATF6α is a hepatic tumour driver restricting immunosurveillance.

Xin Li, Cynthia Lebeaupin, Aikaterini Kadianaki, Clementine Druelle-Cedano, Niklas Vesper, Charlotte Rennert, Júlia Huguet-Pradell, Borja Gomez Ramos, Chaofan Fan, Robert Stefan Piecyk, Laimdota Zizmare, Pierluigi Ramadori, Luqing Li, Lukas Frick, Menjie Qiu, Cangang Zhang, Luiza Martins Nascentes Melo, Vikas Prakash Ranvir, Peng Shen, Johannes Hanselmann, Jan Kosla, Mirian Fernández-Vaquero, Mihael Vucur, Praveen Baskaran, Xuanwen Bao, Olivia I Coleman, Yingyue Tang, Miray Cetin, Zhouji Chen, Insook Jang, Stefania Del Prete, Mohammad Rahbari, Peng Zhang, Timothy V Pham, Yushan Hou, Aihua Sun, Li Gu, Laura C Kim, Ulrike Rothermel, Danijela Heide, Adnan Ali, Suchira Gallage, Nana Talvard-Balland, Marta Piqué-Gili, Albert Gris-Oliver, Alessio Bevilacqua, Lisa Schlicker, Alec Duffey, Kristian Unger, Marta Szydlowska, Jenny Hetzer, Duncan T Odom, Tim Machauer, Daniele Bucci, Pooja Sant, Jun-Hoe Lee, Jonas Rösler, Sven W Meckelmann, Johannes Schreck, Sue Murray, M Celeste Simon, Sven Nahnsen, Almut Schulze, Ping-Chih Ho, Manfred Jugold, Kai Breuhahn, Jan-Philipp Mallm, Peter Schirmacher, Susanne Roth, Nuh Rahbari, Darjus F Tschaharganeh, Stephanie Roessler, Benjamin Goeppert, Bertram Bengsch, Geoffroy Andrieux, Melanie Boerries, Nisar P Malek, Marco Prinz, Achim Weber, Robert Zeiser, Pablo Tamayo, Peter Bronsert, Konrad Kurowski, Robert Thimme, Detian Yuan, Rafael Carretero, Tom Luedde, Roser Pinyol, Felix J Hartmann, Michael Karin, Alpaslan Tasdogan, Christoph Trautwein, Moritz Mall, Maike Hofmann, Josep M Llovet, Dirk Haller, Randal J Kaufman, Mathias Heikenwälder.

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality and there are limited therapies1. Although endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR transducer ATF6α remains unclear2. Here we demonstrate the function of ATF6α as an ER-stress-inducing tumour driver and metabolic master regulator restricting cancer immunosurveillance for HCC, in contrast to its well-characterized role as an adaptive response to ER stress3. ATF6α activation in human HCC is significantly correlated with an aggressive tumour phenotype, characterized by reduced patient survival, enhanced tumour progression and local immunosuppression. Hepatocyte-specific ATF6α activation in mice induced progressive hepatitis with ER stress, immunosuppression and hepatocyte proliferation. Concomitantly, activated ATF6α increased glycolysis and directly repressed the gluconeogenic enzyme FBP1 by binding to gene regulatory elements. Restoring FBP1 expression limited ATF6α-activation-related pathologies. Prolonged ATF6α activation in hepatocytes triggered hepatocarcinogenesis, intratumoural T cell infiltration and nutrient-deprived immune exhaustion. Immune checkpoint blockade (ICB)4 restored immunosurveillance and reduced HCC. Consistently, patients with HCC who achieved a complete response to immunotherapy displayed significantly increased ATF6α activation compared with those with a weaker response. Targeting Atf6 through germline ablation, hepatocyte-specific ablation or therapeutic hepatocyte delivery of antisense oligonucleotides dampened HCC in preclinical liver cancer models. Thus, prolonged ATF6α activation drives ER stress, leading to glycolysis-dependent immunosuppression in liver cancer and sensitizing to ICB. Our findings suggest that persistently activated ATF6α is a tumour driver, a potential stratification marker for ICB response and a therapeutic target for HCC.

DOI: https://doi.org/10.1038/s41586-025-10036-8

Sci Rep. 2026 Feb 04.

PERK inhibition attenuates multi-program cell death through Nrf2/HO-1 activation in diabetic retinopathy with integrated proteomics and functional validation in HRECs.

Like Xie, Xinran Zhang, Min Tian, Min Tang, Qi Zhou, Hongbin Lv.

Keywords: Apoptosis; Diabetic retinopathy; Endoplasmic reticulum stress; Ferroptosis; Human retinal endothelial cells; Nuclear factor erythroid 2-related factor 2; Protein kinase r-like ER kinase; Pyroptosis

DOI: https://doi.org/10.1038/s41598-026-38213-3

Cell Death Discov. 2026 Feb 05.

Activating GCN2 and subsequently the Unfolded Protein Response with the small oral molecule NXP800 delays tumor growth in osteosarcoma.

Emma Racineau, Morgane Lallier, Anaïs Postec, Jérôme Amiaud, Rose-Anne Thépault, Régis Brion, Séverine Battaglia, Céline Charrier, Marie-Anne Colle, Bénédicte Brounais-Le Royer, Marc Baud'huin, Franck Verrecchia, Benjamin Ory, Steven Georges, François Lamoureux.

Osteosarcoma (OS) is the most common primary malignant bone tumor mainly affecting children and young adults. Despite current treatments combining polychemotherapy and surgery, survival rates have remained unchanged for decades, highlighting the need to identify novel therapeutic approaches. NXP800, a newly developed orally available molecule, represents a promising therapeutic option. The therapeutic efficacy of NXP800 was evaluated in vitro and in a preclinical murine xenograft model of OS. RNA-seq analysis and functional assays were conducted to investigate the mechanisms of action and molecular target of NXP800. NXP800 decreases the viability of OS cell lines by blocking proliferation and inducing apoptosis. Mechanistically, NXP800 activates the Unfolded Protein Response (UPR), as demonstrated by eIF2α phosphorylation and ATF4 upregulation. This effect is mediated through the engagement of the Integrated Stress Response (ISR) via the activation of GCN2 kinase. Inhibition of GCN2, either through molecular or pharmacological approaches, abolishes NXP800-induced eIF2α phosphorylation and partially restores OS cell viability. Furthermore, NXP800 activates the IRE1α/JNK/c-Jun pathway while increasing the expression of the pro-apoptotic protein Puma. Finally, NXP800 delays tumor growth in preclinical OS model by promoting apoptosis. This study is a preclinical proof-of-principle of therapeutic efficacy of NXP800 both in vitro and in vivo, highlighting the relevance of targeting GCN2, and consequently activating the ISR and UPR, to induce apoptosis and inhibit tumor progression in OS.

DOI: https://doi.org/10.1038/s41420-026-02941-2

Nat Cell Biol. 2026 Feb 02.

ER remodelling is a feature of ageing and depends on ER-phagy.

Eric K F Donahue, Nathaniel L Hepowit, Elizabeth M Ruark, Alexandra G Mulligan, Brennen Keuchel, Nicholas D Urban, Li Peng, Stedman Stephens, Derek J Johnson, Natalie S Wallace, Lauren P Jackson, Mark H Ellisman, Rafael Arrojo E Drigo, Andrew W Folkmann, Matthias C Truttmann, Jason A MacGurn, Kristopher Burkewitz.

The endoplasmic reticulum (ER) comprises an array of subdomains, each defined by a characteristic structure and function. Although altered ER processes are linked to age-onset pathogenesis, it is unclear whether shifts in ER structure or dynamics underlie these functional changes. Here we establish ER structural and functional remodelling as a conserved feature of ageing across yeast, Caenorhabditis elegans and mammals. Focusing on C. elegans as the exemplar of metazoan ageing, we reveal striking age-related reductions in ER volume across diverse tissues and a morphological shift from rough sheets to tubular ER. This morphological transition corresponds with large-scale shifts in ER proteome composition from protein synthesis to lipid metabolism, a phenomenon conserved in mammalian tissues. We show that Atg8 and ULK1-dependent ER-phagy drives age-associated ER remodelling through tissue-specific factors, including the previously uncharacterized ER-phagy regulator TMEM-131 and the IRE-1-XBP-1 branch of the unfolded protein response. Providing support for a model where ER remodelling is adaptive, diverse lifespan-extending paradigms downscale and remodel ER morphology throughout life. Furthermore, mTOR-dependent lifespan extension in yeast and worms requires ER-phagy, indicating that ER remodelling is a proactive and protective response during ageing. These results reveal ER-phagy and ER dynamics as pronounced, underappreciated mechanisms of both normal ageing and age-delaying interventions.

DOI: https://doi.org/10.1038/s41556-025-01860-1

FEBS Open Bio. 2026 Feb 06.

Differential regulation of ZFAS1 splice variants by endoplasmic reticulum stress in hepatocyte cell lines.

Sébastien Soubeyrand, Paulina Lau, Ruth McPherson.

The suppression of the long noncoding RNA (lncRNA) TRIBAL in hepatocytes was recently shown to affect the expression of pivotal regulators and hundreds of poorly understood or uncharacterized transcripts. The most upregulated transcript corresponded to a predicted splice variant of the lncRNA ZFAS1. Here, we characterize and investigate the role and regulation of ZFAS1 splice variants in liver cell models. New ZFAS1 splice variants were identified, all of which were enriched in the cytoplasm of HepG2 cells. TRIBAL suppression strongly upregulated a low-abundance ZFAS1 variant in hepatocytes but not in hepatoma models. However, preventing the upregulation of the ZFAS1 splice variant did not mitigate the impact of TRIBAL suppression in hepatocytes. ZFAS1 variants were rapidly but differentially increased in response to thapsigargin, which causes endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR). Inhibition of PERK, a central sensor of the UPR, had contrasting impacts on ZFAS1 variants in response to thapsigargin. Moreover, whereas the upregulation of the main ZFAS1 form was reduced by the suppression of the UPR mediators ATF4 and NFE2L2 (also known as NRF2), the other variants were not. Lastly, ZFAS1 suppression decreased cell viability both at baseline and in response to acute thapsigargin treatment. This work identifies novel ZFAS1 variants and uncovers a link between ER stress and ZFAS1 through the UPR.

Keywords: ER stress; HepG2; TRIBAL; ZFAS1; hepatocytes; unfolded protein response

DOI: https://doi.org/10.1002/2211-5463.70185

Immunology. 2026 Feb 02.

Comment on: Pasco ST Et Al. "Challenge-Specific Modulation of Responses to Adjuvant-Induced Innate Immune Memory".

M Vijayasimha, M Srikanth.

This schematic illustrates the role of endoplasmic reticulum (ER) stress and PERK inhibition in modulating pancreatic cancer cell fate. ER stress activates the PERK pathway, which contributes to tumor cell survival. Pharmacologic inhibition of PERK, as depicted, leads to two downstream effects: decreased cellular proliferation and increased apoptosis. The diagram highlights the therapeutic potential of PERK-targeting strategies in disrupting cancer cell growth and promoting programmed cell death.

DOI: https://doi.org/10.1111/imm.70118

Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2526598123

Structural basis for pseudokinase-mediated regulation of GCN2 in the integrated stress response.

Yixin Liu, Jagannath Misra, Debarshi Ryan Bhowmik, Brady O'Boyle, Kirk A Staschke, Natarajan Kannan, Ronald C Wek, Natalia Jura.

The general control nonderepressible 2 (GCN2) is a conserved stress-responsive protein that plays a critical role in restoring cellular homeostasis in the integrated stress response (ISR). In response to amino acid starvation or ribosome stalling and collisions, GCN2 phosphorylates the translation initiation factor eIF2α, conferring translational control to alleviate stress. GCN2 is a multidomain protein, containing a tandem kinase domain (KD) and a catalytically inactive pseudokinase domain (ψKD). Stress-induced activation of the kinase domain requires allosteric regulation and dimerization mediated by its regulatory domains. While the pseudokinase domain is essential for GCN2 function in yeast, its mechanistic role remains unclear and underexplored in other organisms. Here, we present the first crystal structure of the human GCN2 ψKD, revealing its distinct structural features. The structure visualizes an insertion N-terminal to helix αC unique to the GCN2 ψKD that interacts with the pseudoactivation loop, stabilizing an inactive conformation. Further structural analysis shows that the ψKD forms a dimer in the crystal lattice via a network of hydrophobic and electrostatic interactions spanning both the N- and C-lobes. Mutations that disrupt the dimer interface reduced downstream ATF4 expression that is important for stress adaptation, underscoring the functional significance of the GCN2 ψKD dimer in regulating GCN2 activity. Complementary AI-guided structure predictions indicate that the dimeric GCN2 ψKD architecture is conserved across evolution. These results support the role of ψKD dimerization as a regulatory feature in GCN2-mediated ISR signaling.

Keywords: ATF4 translation; GCN2; dimerization; integrated stress response; pseudokinase

DOI: https://doi.org/10.1073/pnas.2526598123