bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–04–26
thirteen papers selected by
Susan Logue, University of Manitoba
  1. Pharmacological inhibition of the PERK pathway modulates hepatocellular carcinoma growth and immune signaling.
  2. ER stress: A putative therapeutic target for diabetes mellitus.
  3. The host protein SSR4 mediates PRRSV-induced endoplasmic reticulum stress via interaction with Nsp2.
  4. GRP78 Selective Inhibitors From a Direct-to-Biology Strategy.
  5. UFL1 deficiency impairs skeletal muscle development by activating PERK/eIF2α/ATF4/CHOP pathway-dependent apoptosis.
  6. Multifaceted role of CNPY2 beyond ER stress: Disease implications and therapeutic potential.
  7. The transcription factor Rlm1 couples the MAPK Slt2/ERK1 pathway to the IRE1-driven unfolded protein response.
  8. Polyploidy reprograms epithelial cells for motility and phagocytosis via stress signaling.
  9. Bacteria use P-body condensates to attenuate host translation during infection.
  10. Overcoming ADC resistance in advanced colorectal cancer by dual targeting of TROP2 and PERK to suppress Wnt/β-catenin signaling.
  11. Zinc-redox crosstalk regulates proteostasis in the endoplasmic reticulum.
  12. Pyrazolylpyrimidinamines Decorated via Petasis Reaction as Small-Molecule Activators of the RNA-Degrading Ribonuclease IRE1α.
  13. HOOK2 downregulation compromises the tumorigenic and stemness properties of ovarian cancer cells by increasing endoplasmic reticulum stress.
  1. FEBS Open Bio. 2026 Apr 21.
    Pharmacological inhibition of the PERK pathway modulates hepatocellular carcinoma growth and immune signaling.
    Ada Lerma-Clavero, Maria Kopsida, Nathalie Arendt, Hans Lennernäs, Markus Sjöblom, Femke Heindryckx.
      The unfolded protein response (UPR) plays an important role in tumor progression and cellular stress adaptation. In hepatocellular carcinoma (HCC), pharmacological inhibition of the protein kinase R-like endoplasmic reticulum kinase (PERK) is a potential therapeutic strategy, yet its effects on tumor growth and the microenvironment remain unclear. We investigated the selective PERK inhibitor AMG PERK 44 in a diethylnitrosamine (DEN)-induced mouse model of advanced HCC. Tumor burden, proliferation, fibrosis, immune-related gene expression, and ER stress signaling were assessed alongside analyses of single-cell RNA-sequencing data from HCC mouse models and liver-specific PERK knockout mice. Our results show that AMG PERK 44 did not alter tumor number nor cause a decrease in tumor area and proliferation. Furthermore, fibrotic burden was unchanged, although fibrosis architecture and stromal gene expression (TGF-β, CTGF, F4/80) were modified. Despite PERK inhibition, the expression of ER stress associated genes (CHOP, EIF2AK3, ERdj4) increased. Single-cell analysis revealed context-dependent PERK activity, highest in dendritic cells and macrophages under inflammatory and tumor conditions, while PERK knockout livers showed impaired UPR responses after tunicamycin treatment. Finally, AMG PERK 44 did not enhance idarubicin efficacy and caused no major off-target effects. These findings highlight the context-dependent role of PERK in the HCC microenvironment and its implications for targeting UPR pathways in liver cancer. Impact statement This study provides an evaluation of PERK as a therapeutic target in hepatocellular carcinoma by demonstrating that its inhibition does not produce the anticipated anti-tumor effects in advanced disease, but instead exerts nuanced, context-dependent influences on the tumor microenvironment.
    Keywords:  AMG PERK44; ER stress; PERK; carcinogenesis; fibrosis; hepatocellular carcinoma; idarubicin; inflammation
    DOI:  https://doi.org/10.1002/2211-5463.70252
  2. Biochem Biophys Res Commun. 2026 Apr 15. pii: S0006-291X(26)00537-1. [Epub ahead of print]818 153773
    ER stress: A putative therapeutic target for diabetes mellitus.
    Eveline M Anto, Adheena M, P Jayamurthy.
      Diabetes mellitus (DM) is a growing global health concern, with escalating prevalence and a significant impact on morbidity, mortality, and healthcare economics. With over half a billion people affected worldwide, the need for innovative and effective treatment strategies is urgent. Here, we review the current pharmacological landscape for DM management, detailing various classes of antidiabetic drugs and providing a comprehensive overview of existing treatment modalities. Despite these treatments, there is a critical need for new therapeutic targets, given the rising disease prevalence and the substantial economic burden of diabetes care. In this context, the involvement of endoplasmic reticulum (ER) stress in the progression of DM is examined as a promising avenue for pharmacological targeting. The role of ER stress as an emerging therapeutic target in managing DM is highlighted here. In conclusion, the review underscores the importance of innovative research in identifying and validating new therapeutic targets, such as ER stress, to improve the management of DM and mitigate its global health impact.
    Keywords:  Diabetes; ER stress; Therapeutic target; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153773
  3. J Virol. 2026 Apr 23. e0026626
    The host protein SSR4 mediates PRRSV-induced endoplasmic reticulum stress via interaction with Nsp2.
    Yingchao Li, Hongyan Gao, Zhong Liu, Man Lu, Yang Shen, Yajing Xing, Yu Wang, Xiaotong Wu, Pingping Yang, Hongjie Yuan, Yanmeng Hou, Yumei Cai, Baoquan Li, Yihong Xiao.
      Porcine reproductive and respiratory syndrome (PRRS) is a major economic burden to the global swine industry. Here, we identify the endoplasmic reticulum (ER) translocon component SSR4 as a critical host factor co-opted by PRRSV. We demonstrate that the viral non-structural protein Nsp2 physically interacts with SSR4 via its PLP2 and hypervariable domains and selectively upregulates its expression during infection by prolonging its protein half-life. Functional studies revealed that SSR4 is a proviral factor essential for efficient PRRSV replication. Mechanistically, SSR4 is required for the full activation of the PRRSV-induced ER stress response, specifically modulating the PERK-eIF2α and IRE1α-XBP1 axes of the unfolded protein response. Notably, Nsp2 itself acts as a key inducer of ER stress and mediates the upregulation of SSR4, suggesting a potential feed-forward loop that sustains a virus-favorable ER environment. This relationship is finely balanced, as pharmacological disruption of ER homeostasis using either the inducer tunicamycin (TU) or the chemical chaperone 4-phenylbutyric acid (4-PBA) potently inhibited viral replication. Importantly, TU and another inducer, dithiothreitol, exhibited potent, broad-spectrum antiviral activity against multiple PRRSV genotypes in both cell lines and primary porcine alveolar macrophages. Our study delineates a novel pathogenesis model where PRRSV Nsp2 hijacks SSR4 to engineer a proviral ER stress niche. The Nsp2-SSR4-ER stress axis represents a promising target for the development of broad-spectrum antiviral strategies against PRRS.IMPORTANCEThis study provides significant insights into porcine reproductive and respiratory syndrome virus (PRRSV) pathogenesis by identifying a novel and specific virus-host interface. We demonstrate that PRRSV, through its Nsp2 protein, hijacks a specific component of the host endoplasmic reticulum (ER) translocon SSR4 to orchestrate a tailored ER stress response conducive to viral replication. This mechanism is distinct from a general disruption of the TRAP complex, highlighting a precise viral strategy. Furthermore, the finding that pharmacological agents, which dysregulate this hijacked pathway-particularly ER stress inducers-act as potent, broad-spectrum antivirals challenges the conventional view of ER stress as a uniformly host-protective response. Our work not only uncovers a key molecular determinant of PRRSV replication but also validates the Nsp2-SSR4-ER stress axis as a promising and novel target for the development of much-needed, broad-spectrum therapeutic interventions against this economically devastating swine pathogen.
    Keywords:  ER stress; Nsp2; PRRSV; SSR4; antiviral drugs
    DOI:  https://doi.org/10.1128/jvi.00266-26
  4. Angew Chem Int Ed Engl. 2026 Apr 23. e23960
    GRP78 Selective Inhibitors From a Direct-to-Biology Strategy.
    Xiaoyi Zhu, Carlee A Trindl, Qiu Li, Haofeng Ye, Lewis Alexander, Dichun Huang, Yongyi Wei, Vyana Trieu, Ben N Stansfield, Aikseng Ooi, Yang Yang-Hartwich, Donna D Zhang, Eli Chapman.
      Because cancer cells have heightened protein homeostasis (proteostasis) requirements, there is interest in targeting proteostasis machinery, including the 70 kDa heat shock proteins (HSP70s), as potential cancer therapeutics. However, studies have shown that the HSP70 family is differentially regulated across cancers, and global targeting may produce unwanted toxicities. For this reason, our lab has focused on isoform-selective targeting of HSP70s, including the endoplasmic reticulum-resident HSP70, GRP78 (HSPA5 or BiP). GRP78 is a central component of protein homeostasis in the secretory system and is the principal regulator of the unfolded protein response (UPR). Here, we report the use of a direct-to-biology (D2B) strategy to optimize a dipeptide-based scaffold that binds selectively to GRP78, relative to the other canonical HSP70s. We show that our lead compound, 12, potently and selectively inhibits GRP78, binds to the substrate binding pocket, kills A549 lung cancer cells in 2D (grown as a monolayer) and 3D (grown as spheroids) cultures, engages GRP78 in cells, and that GRP78 inhibition is responsible for the mode of action. This work represents the first GRP78-selective inhibitor that inhibits substrate binding.
    Keywords:  BiP; ER stress; GRP78; HSP70; HSPA5; lung cancer; proteostasis
    DOI:  https://doi.org/10.1002/anie.202523960
  5. Cell Signal. 2026 Apr 20. pii: S0898-6568(26)00202-0. [Epub ahead of print] 112550
    UFL1 deficiency impairs skeletal muscle development by activating PERK/eIF2α/ATF4/CHOP pathway-dependent apoptosis.
    Junjie Xu, Mali Guo, Ping Li, Fengwei Li, Kang Zhou, Fanghui Chen, Yafei Cai.
      Ubiquitin-like modifier 1 ligating enzyme 1 (UFL1), the essential E3 ligase in the UFMylation system, plays a crucial yet undefined role in skeletal muscle development. In this study, our primary objective was to elucidate the function and molecular mechanism of UFL1 in myoblast survival and myofiber development. UFL1 deficiency in mice exacerbated ultra structural damage in myofibers and significantly increased myoblast apoptosis both in vivo and in vitro, as evidenced by upregulation of Cleaved Poly (ADP-ribose) polymerase (cleaved PARP), Cleaved Cysteinyl aspartate specific proteinase 3 (cleaved Caspase-3), and BCL2-associated X protein (BAX), alongside downregulation of B-cell lymphoma 2 (BCL2). Mechanistically, UFL1 knockout robustly activated the ER stress response, characterized by a significant increase in mRNA levels of Glucose-regulated protein 78 (GRP78), Activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), as well as specific activation of the Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)/Eukaryotic translation initiation factor 2 subunit alpha (eIF2α)/ATF4/CHOP signaling axis. Conversely, UFL1 overexpression effectively suppressed this pathway and reduced apoptosis. Notably, treatment with the PERK inhibitor GSK2606414 successfully reversed the UFL1 deficiency-induced upregulation of p-PERK, p-eIF2α, ATF4, and CHOP and rescued the apoptotic phenotype. Our study demonstrates for the first time that UFL1 is a critical regulator for maintaining myoblast survival and normal myofiber development, acting partly through suppressing the PERK-mediated ER sress. These findings provide novel insights into the pathogenesis of muscle developmental disorders and suggest UFL1 as a potential therapeutic target.
    Keywords:  Apoptosis; ER stress; PERK/eIF2α/ATF4/CHOP; Skeletal muscle; UFL1
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112550
  6. Cell Stress. 2026 ;10 19-31
    Multifaceted role of CNPY2 beyond ER stress: Disease implications and therapeutic potential.
    Shima Ebadollahibaruq, Lingbin Meng, Feng Hong.
      Canopy homolog protein 2 (CNPY2), an endoplasmic reticulum (ER) luminal protein exhibits broad tissue distribution and regulates cellular homeostasis, including unfolded protein responses (UPR), mitochondrial dynamics, oxidative stress, and apoptosis. Beyond its role in cancer progression through pathways such as NF- κ B, AKT/GSK3 β , PI3K/Akt/mTOR and HIF-1 α , promoting epithelial-mesenchymal transition (EMT), tumor survival and metastasis, CNPY2 is also critical in non-cancer conditions. In neurodegenerative disorders including Parkinson's and Huntington's, it exerts neuroprotective role by reducing oxidative stress and mitochondrial dysfunction. In cardiovascular tissues, CNPY2 leads to hypoxia-driven angiogenesis, tissue repair, and ischemia-reperfusion protection. Moreover, recent meta-analyses have linked CNPY2 downregulation with Keratoconus pathogenesis, further highlighting its tissue- specific roles. Hence, this review meticulously dissects CNPY2's structural characteristics, expression patterns, and biological functions across cancer, cardiovascular disease, inflammation and neurological disorders, emphasizing its role on tumor initiation, microenvironmental stress, and chemoresistance, and evaluating its potential as a therapeutic target.
    Keywords:  Canopy homolog protein 2; Endoplasmic reticulum stress; cancer; cardiovascular disease; neurodegenerative disease; tumor microenvironment; unfolded protein responses
    DOI:  https://doi.org/10.15698/cst2026.03.316
  7. Commun Biol. 2026 Apr 21.
    The transcription factor Rlm1 couples the MAPK Slt2/ERK1 pathway to the IRE1-driven unfolded protein response.
    Anish Chakraborty, Saswata Chakrabarty, Jagadeesh Kumar Uppala, Kimberly Ann Mayer, Anna J Evans, Jasmine George, Chandrima Ghosh, Ritisha Dey, Franca Ohikhuare, Shama Mirza, An Phu Tran Nguyen, Nadège Gouignard, Pradeep Chaluvally-Raghavan, Madhusudan Dey.
      Unfolded protein response (UPR) is a conserved cellular strategy that enhances the protein folding capacity of cells under stress conditions. In Saccharomyces cerevisiae, the dual kinase RNase IRE1 initiates the UPR by catalyzing the cytosolic splicing of HAC1 mRNA, a process conserved in humans where IRE1 splices XBP1 mRNA. The spliced HAC1/XBP1 mRNA yields a transcription factor that upregulates the expression of protein-folding enzymes and chaperones, thereby boosting the cell's ability to cope with unfolded proteins. Our study demonstrates that the UPR involves two distinct phases. The early phase operates predominantly through the canonical IRE1 signaling pathway, while the later phase involves additional regulation by the MAP kinase Slt2 or its human ortholog ERK1/ERK2/ERK5 and the downstream target the MADS-box transcription factor Rlm1 (an ortholog of human MEF2C). We further show that Slt2 promotes IRE1 expression through Rlm1. Together, these findings reveal a previously unrecognized crosstalk between the MAPK and IRE1-mediated arm of the UPR.
    DOI:  https://doi.org/10.1038/s42003-026-10090-6
  8. J Cell Biol. 2026 May 04. pii: e202507096. [Epub ahead of print]225(5):
    Polyploidy reprograms epithelial cells for motility and phagocytosis via stress signaling.
    Youfang Zhou, Xianfeng Wang, Xiaochao Tan, Shingo Nara, Yi-Chun Huang, Yoichiro Tamori, Wu-Min Deng.
      Polyploidy, an increase in cellular genome content, is a conserved developmental program and a hallmark of malignant cancer, yet its impact on cell behavior remains poorly understood. Here, we show that induction of polyploidy in otherwise diploid cells causes intrinsic stress that reprograms cellular physiology to promote motility-like and phagocytic behaviors. Using the Drosophila wing imaginal disc, we find that induced polyploidy enhances membrane dynamics and triggers dynamic cell behavior through a ROS-JNK stress axis activated by ER stress. These cells also acquire phagocytic activity, engulfing both dead and live neighboring cells in developmental and tumor contexts. This stress-induced reprogramming is conserved in induced poly-aneuploid mammalian cancer cells, linking increased genomic content to metastatic traits. Our findings uncover a conserved role for induced polyploidy in driving stress-responsive and immune cell-like behaviors, revealing how elevated ploidy can reshape epithelial function during development and disease.
    DOI:  https://doi.org/10.1083/jcb.202507096
  9. Sci Adv. 2026 Apr 24. 12(17): eaec4477
    Bacteria use P-body condensates to attenuate host translation during infection.
    Manuel González-Fuente, Nico Schulz, Alibek Abdrakhmanov, Thorben Krüger, Gaiea Izzati, Shanshuo Zhu, Gautier Langin, Paul Gouguet, Mirita Franz-Wachtel, Boris Macek, Anders Hafrén, Yasin Dagdas, Suayib Üstün.
      Pathogens use sophisticated strategies to modulate host protein homeostasis by targeting proteolytic pathways, but their impact on protein synthesis remains elusive. We report that pathogenic bacteria Pseudomonas syringae (Pst) targets ribonucleoprotein condensates, known as processing bodies (P-bodies), to attenuate host translation through two effectors with liquid-like properties. We uncovered a previously unknown link that Pst-mediated repression of the endoplasmic reticulum stress response is required for P-body assembly. Furthermore, we identify a functional link between P-bodies and autophagy, demonstrating that autophagic clearance of P-bodies is crucial for maintaining the balance between translationally active and inactive messenger RNAs. Together, our findings provide insights on how host translation is attenuated by bacteria to dampen plant immunity and uncover unknown connections between ER stress responses and autophagy with P-body dynamics.
    DOI:  https://doi.org/10.1126/sciadv.aec4477
  10. Cell Rep Med. 2026 Apr 23. pii: S2666-3791(26)00186-2. [Epub ahead of print] 102769
    Overcoming ADC resistance in advanced colorectal cancer by dual targeting of TROP2 and PERK to suppress Wnt/β-catenin signaling.
    Jie Liu, Mei Li, Jianming Huang, Yujie Xia, Guanfeng Jiang, Hong'an Zhang, Jiaxin Yang, Mingfeng Jiang, Yalan Liu, Yilun Luo, Liefeng Wang, Shuyong Zhang.
      Targeted therapy for advanced colorectal cancer (CRC) remains a significant unmet clinical need. Here, we investigate the mechanism of the anti-TROP2 antibody-drug conjugate IMMU132, delivering SN-38 to induce TOP1-mediated DNA damage and cytotoxicity. We further discover that it concurrently suppresses the PERK-eIF2α-ATF4 axis of the unfolded protein response, a key adaptive survival pathway activated by therapy-induced endoplasmic reticulum (ER) stress. This dual action of direct killing and stress adaptation disruption may dismantle a key resistance mechanism. Furthermore, combining IMMU132 with the PERK inhibitor GSK2606414 yields potent synergy across various CRC preclinical models. Mechanistically, this synergy stems from the enhanced suppression of ER stress and the oncogenic Wnt/β-catenin pathway. Thus, our findings reveal that co-targeting the DNA damage response, the PERK pathway, and the Wnt/β-catenin pathway is a promising strategy to overcome resistance to TROP2-directed antibody-drug conjugates (ADCs) in advanced CRC, providing a rational framework for combination therapies.
    Keywords:  PERK; TROP2; antibody drug conjugate; colorectal cancer; endoplasmic reticulum stress; synergistic effect
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102769
  11. Nat Commun. 2026 Apr 22.
    Zinc-redox crosstalk regulates proteostasis in the endoplasmic reticulum.
    Yuta Amagai, Chihiro Arai, Wakana Yamamoto, Satoshi Watanabe, Toshiyuki Kowada, Roberto Sitia, Jun Hoseki, Shin Mizukami, Masaki Matsumoto, Kenji Inaba.
      Zinc homeostasis is crucial for various biological processes, including gene regulation, signal transduction, and proteostasis. ZIP7 is a membrane transporter that exports zinc ions (Zn2+) from the lumen of the endoplasmic reticulum (ER) to the cytosol, and its dysfunction causes ER stress, although the underlying mechanism remains unclear. Here, we show that ZIP7 inhibition increases the labile Zn2+ concentration in the ER to micromolar levels, approximately 106 times higher than its steady-state level. Such abnormally high Zn2+ concentrations disrupt the function and trafficking of the Zn2+-dependent chaperone ERp44 at the ER-Golgi interface. In vitro assays using recombinant proteins demonstrated that Zn2+ inhibits the Ero1α-PDI oxidative system, and that ERp44 enhances this inhibitory effect. Consequently, the ER redox environment becomes more reducing, severely impairing the oxidative folding of key membrane receptors such as Notch1 and EGFR. These findings reveal the essential role of zinc homeostasis in redox-dependent proteostasis within the ER.
    DOI:  https://doi.org/10.1038/s41467-026-72250-w
  12. ACS Bio Med Chem Au. 2026 Apr 15. 6(2): 118-129
    Pyrazolylpyrimidinamines Decorated via Petasis Reaction as Small-Molecule Activators of the RNA-Degrading Ribonuclease IRE1α.
    Amrutha K Avathan Veettil, Yang Liu, Leon Wagner, Oguz Hastürk, Nguyen Song Thu Huynh, Giorgia Mancino, Maria Beerbaum, Peng Wu.
      The multicomponent Petasis boron-Mannich reaction (PR) enables the generation of functionalized amines that are of biological interest. Here, we demonstrated that a series of pyrazolylpyrimidinamines decorated via PR are new small-molecule activators of the dual kinase and ribonuclease RNA-degrading protein inositol-requiring enzyme 1α (IRE1α), which is an essential effector in the unfolded protein response associated with many human diseases. Compound SH4 was identified via a FRET assay and showed potent activity in activating the IRE1α ribonuclease (RNase) activity, inducing increased XBP1 mRNA splicing, and inducing Bloc1s1 mRNA degradation. Based on a binding mode analysis, the following series of PR-decorated functionalized amines was further probed as IRE1α RNase activators. One PR-derived compound, AK177, showed nanomolar activating potency in biochemical assays but minimal activities in cellular evaluations. Overall, we present here a series of pyrazolylpyrimidinamines as new small-molecule activators of the IRE1α RNase activity, which served as the first examples of applying PR in accessing bioactive compounds targeting the kinase domain of a ribonuclease involved in mRNA cleavage and splicing.
    Keywords:  Petasis reaction; RNA degradation; pyrimidinamine; ribonuclease; small-molecule activator
    DOI:  https://doi.org/10.1021/acsbiomedchemau.5c00161
  13. Cell Death Dis. 2026 Apr 24.
    HOOK2 downregulation compromises the tumorigenic and stemness properties of ovarian cancer cells by increasing endoplasmic reticulum stress.
    Elisa Suárez-Martínez, Asunción Espinosa-Sánchez, Sander R Piersma, Thang V Pham, Irene V Bijnsdorp, Connie R Jimenez, Amancio Carnero.
      Ovarian cancer stands out as one of the tumors with a high mortality rate in women. Therefore, the search for new therapeutic targets is essential to enhance patient prognosis. There is evidence suggesting that HOOK2, an adaptor protein involved in microtubule transport, may play a role in cancer, particularly ovarian cancer. This study examines the role of HOOK2 in the progression of ovarian tumors. The findings reveal that a decrease in HOOK2 levels leads to diminished growth and cellular migration in ovarian cancer cells, impeding the in vivo formation of tumors. The reduction of HOOK2 is associated with both an increase in endoplasmic reticulum stress and an elevation in cell death, the latter likely caused by the activation of the unfolded protein response. Moreover, the study observes that the decrease in HOOK2 diminishes the properties of cancer stem cells in ovarian cancer, possibly due to the increase in cell death specifically found within these stem cells. Given the profound impact of reduced HOOK2 levels on ovarian cancer cells, this gene emerges as a promising therapeutic strategy for treating ovarian cancer patients.
    DOI:  https://doi.org/10.1038/s41419-026-08763-5
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