bims-unfpre 2026-07-12 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–07–12
eleven papers selected by
Susan Logue, University of Manitoba

Broad Roles of Endoplasmic Reticulum Stress Sensors Activated by Diverse Pathophysiological Stimuli.
Bioinformatic pipeline to identify candidate mRNA transcripts targeted by the putative Regulated Ire1-Dependent Decay pathway of Dictyostelium discoideum .
Pharmacological modulation of ATF6: exploiting a stress-integrative node to overcome drug resistance.
Endoplasmic Reticulum Stress-Induced Endothelial Cell Pyroptosis Contributes to Pulmonary Vascular Remodeling and Pulmonary Arterial Hypertension via IRE1α/Caspase-3/GSDME Pathway.
Inhibition of SIK2 and SIK3 induces adaptive ER-phagy and creates a therapeutic vulnerability in ovarian cancer.
ACSL3 inhibits ferroptosis in gastric cancer through the activation of unfolded protein response following endoplasmic reticulum stress.
FGF21 connects ER stress to sulfide signaling to enhance cellular resilience.
IFNα and bleomycin-induced DNA damage activate distinct stress responses in human islets and induced pluripotent stem cell-derived islet cells.
Proteostasis Rebalancing by LET-607 Deficiency Promotes Longevity.
Mechanosensing at the endoplasmic reticulum by IRE1.
Machine learning-driven development of a novel unfolded protein response-related gene signature for predicting lung adenocarcinoma patient prognosis.

Front Biosci (Landmark Ed). 2026 Jun 25. 31(6): 50701

Broad Roles of Endoplasmic Reticulum Stress Sensors Activated by Diverse Pathophysiological Stimuli.

Kenshiro Fujise, Himari Kimura, Tomoki Tsuji, Yasunao Kamikawa, Kazunori Imaizumi, Atsushi Saito.

  The endoplasmic reticulum (ER) stress response is a critical cellular program that maintains proteostasis and membrane homeostasis through the activation of the ER stress sensor proteins inositol-requiring enzyme 1 (IRE1), protein kinase R-like ER kinase (PERK), activating transcription factor 6 (ATF6), and old astrocyte specifically induced substance (OASIS) family proteins. These sensors, canonically understood as transducers of the unfolded protein response (UPR), respond to the accumulation of misfolded proteins in the ER lumen as a result of ER luminal Ca2+ depletion, defective disulfide bond formation, dysregulated glycosylation, or inhibition of ER-associated degradation. However, recent conceptual advances have reshaped understanding of these classical mechanisms, by revealing multiple non-canonical pathways that operate independently of luminal proteotoxicity. Emerging evidence highlights the roles of ER stress sensors in integrating diverse stimuli, including the integrated stress response, lipid bilayer stress, mitochondria-ER contact, and the DNA damage response. Herein, we discuss how these ER stress sensors function as multidimensional signaling hubs for proteotoxic, metabolic, and genomic stresses, and consequently modulate pathophysiological cellular outcomes. Finally, we examine current knowledge regarding both canonical and non-canonical modes of ER stress sensor activation, and we discuss how these mechanisms expand the functional scope of ER stress signaling in physiological regulation and diseases.

Keywords:  ER stress sensors; endoplasmic reticulum (ER); unfolded protein response (UPR)

DOI:  https://doi.org/10.31083/FBL50701
MicroPubl Biol. 2026 ;2026

Bioinformatic pipeline to identify candidate mRNA transcripts targeted by the putative Regulated Ire1-Dependent Decay pathway of Dictyostelium discoideum .

Connor Bingham, Elias Taylor-Cornejo.

Inositol-requiring protein 1 (Ire1) is a eukaryotic stress sensor that counteracts the buildup of unfolded proteins in the endoplasmic reticulum (ER) by activating the Unfolded Protein Response (UPR) via a specific ribonuclease (RNase) activity. The amoeba Dictyostelium discoideum relies on an ire1 ortholog, ireA , to survive ER stress, but the mRNA transcripts targeted by the IreA ribonuclease remain unknown. In this work, we developed a bioinformatic pipeline that identified 21 mRNA transcripts of D. discoideum that contain a consensus Ire1 cut site found within a secondary mRNA hairpin loop structure and have the potential to be cut by IreA.

DOI: https://doi.org/10.17912/micropub.biology.002098
Drug Discov Today. 2026 Jul 09. pii: S1359-6446(26)00139-X. [Epub ahead of print] 104734

Pharmacological modulation of ATF6: exploiting a stress-integrative node to overcome drug resistance.

Saeid Ghavami, Mahmood Aghaei.

  Activating transcription factor 6 (ATF6), a major arm of the unfolded protein response (UPR), functions as an integrative regulator of cellular adaptation. Beyond proteostasis, ATF6 coordinates redox balance, autophagy, apoptosis, and lipid metabolism. In cancer, aberrant ATF6 signaling promotes proliferation, chemoresistance, ferroptosis evasion, and genome stability through proteolytic activation inflammatory coupling, and post-translation regulation. Crucially, human ATF6 loss‑of‑function mutations cause a blindness-deafness syndrome poorly recapitulated in mice, highlighting potential safety concerns for systemic inhibition. In this review, we summarize ATF6 activation mechanisms, its crosstalk with autophagy and apoptosis, and pharmacological strategies, emphasizing rational combination therapies to overcome drug resistance while preserving physiological homeostasis.

Keywords:  ATF6; ER stress; autophagy; cancer progression; combination therapy; drug resistance

DOI:  https://doi.org/10.1016/j.drudis.2026.104734
J Am Heart Assoc. 2026 Jul 10. e043577

Endoplasmic Reticulum Stress-Induced Endothelial Cell Pyroptosis Contributes to Pulmonary Vascular Remodeling and Pulmonary Arterial Hypertension via IRE1α/Caspase-3/GSDME Pathway.

Xue-Yang Luo, Xue-Chun Li, Xiao Fu, Yu-Yang Tian, Xin-Yi Li, Zhen Zhang, Alex F Chen.

   BACKGROUND: Endothelial cell (EC) injury is regarded as the initiating trigger of pulmonary arterial hypertension (PAH). Excessive endoplasmic reticulum (ER) stress could cause early damage to ECs with subsequent cell death. Pyroptosis leads to EC damage and accelerates PAH progression. However, whether and how ER stress plays a role in regulating EC pyroptosis, especially in PAH progression, remains unclear.
METHODS: The activation level of ER stress and endothelial pyroptosis were assessed in the lungs of a PAH model. Pharmacological inhibitors, small-interfering RNA, and specific inhibitors were used to explore the role and the mechanism of ER stress in regulating EC pyroptosis in PAH in vivo and in vitro, respectively.
RESULTS: ER stress and endothelial pyroptosis were activated in the early stage of monocrotaline-induced PAH rats. Inhibition of ER stress suppressed the activation of the endothelial GSDME (gasdermin E) in PAH rats. Prolonged and severe ER stress increased the level of the GSDME-NT (N-terminal of gasdermin E) and LDH (lactic dehydrogenase) release in ECs. Silencing GSDME or caspase-3 reversed the effect of ER stress-induced EC pyroptosis. Mechanistically, the IRE1α (inositol-requiring kinase 1α) kinase activity mediated the activation of ER stress-triggered caspase-3/GSDME. Inhibition of the IRE1α kinase activity by KIRA6 (IRE1α kinase inhibitor) treatment alleviated the development of PAH by inhibiting caspase-3/GSDME-mediated endothelial pyroptosis and subsequent endothelial integrity disruption.
CONCLUSIONS: These results demonstrated the critical role of prolonged and unresolved ER stress-induced IRE1α activation in modulating EC pyroptosis, leading to early endothelial cell injury and the acceleration of PAH progression.

Keywords:  endoplasmic reticulum stress; inositol‐requiring enzyme 1 α; pulmonary arterial endothelial cells; pulmonary arterial hypertension; pyroptosis

DOI:  https://doi.org/10.1161/JAHA.125.043577
Res Sq. 2026 Jul 01. pii: rs.3.rs-9933879. [Epub ahead of print]

Inhibition of SIK2 and SIK3 induces adaptive ER-phagy and creates a therapeutic vulnerability in ovarian cancer.

Zhen Lu, Rumeysa Ozyurt, Gamze Bildik, Weiqun Mao, Hailing Yang, Robert Bast.

Cancer cells depend on protein quality control pathways to survive intrinsic and microenvironmental stress. Endoplasmic reticulum (ER)-selective autophagy (ER-phagy) maintains ER homeostasis by eliminating damaged ER and misfolded protein aggregates during ER stress. How ER stress-induced ER-phagy is regulated in cancer remains poorly understood. Salt-inducible kinases SIK2 and SIK3 (SIK2/3) are serine/threonine kinases implicated in metabolic regulation and cancer cell survival, but their roles in ER stress signaling and ER-phagy have not previously been studied. Here, we show that genetic or pharmacologic inhibition of SIK2/3 induces proteotoxic stress and activates the unfolded protein response through the PERK and IRE1 pathways, with predominant engagement of PERK and its downstream effector ATF4. SIK2/3 inhibition promotes ER-phagy by upregulating the ER-phagy receptor CCPG1 in an ATF4-dependent manner and increasing autophagic flux, thereby enabling cancer cell survival under stress. Disruption of this adaptive response results in the accumulation of polyubiquitinated protein aggregates, induction of CHOP, and apoptotic cell death in ovarian cancer cells. Importantly, combined treatment with the dual SIK2/3 inhibitor GRN-300 and the autophagy inhibitor chloroquine synergistically enhanced proteotoxic stress, reduced cell viability (combination index < 0.9), and triggered CHOP-dependent apoptosis. In ovarian cancer xenograft models, GRN-300 plus chloroquine markedly suppressed tumor growth and significantly prolonged survival compared with either monotherapy. Together, these findings identify SIK2/3 as key regulators of ER stress-induced ER-phagy and reveal a targetable stress-adaptation pathway that can be exploited therapeutically in ovarian cancer.

DOI: https://doi.org/10.21203/rs.3.rs-9933879/v1
Cell Death Dis. 2026 Jul 07.

ACSL3 inhibits ferroptosis in gastric cancer through the activation of unfolded protein response following endoplasmic reticulum stress.

Honglei Wang, Jie Jiao, Wenshuo Yang, Danping Sun, Meng Wei, Guorui Sun, Zhibo Yan, Yize Liang, Zewei Cheng, Yongqi Yan, Menghui Wang, Yangjia Li, Xiaohan Cui, Wenbin Yu.

The long-chain acyl-CoA synthetase (ACSL) family has been associated with tumor progression across various cancer types. However, the function of the ACSL family in gastric cancer (GC) remains poorly understood. Comprehensive investigations employing in vivo and in vitro experiments demonstrate that ACSL3 suppresses ferroptosis and drives GC progression. Mechanistically, ACSL3 facilitated YY1 nuclear translocation, triggering endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response (UPR). Genome-wide binding analysis revealed that YY1 directly binds to the USP37 promoter, enhancing its transcriptional activation. Furthermore, a novel interaction was identified between USP37 and PERK, a pivotal UPR regulator, wherein USP37 mediates K29-linked deubiquitination of PERK. PERK stabilization upregulated SLC7A11 expression, thereby inhibiting ferroptosis and promoting tumor progression. Collectively, the findings establish a molecular cascade wherein ACSL3 mediates ER stress-mediated UPR activation through the YY1/USP37/PERK axis, suppressing ferroptosis and accelerating GC progression, identifying ACSL3 as a potential therapeutic target for GC treatment.

DOI: https://doi.org/10.1038/s41419-026-09068-3
Cell Metab. 2026 Jul 07. pii: S1550-4131(26)00235-4. [Epub ahead of print]38(7): 1255-1257

FGF21 connects ER stress to sulfide signaling to enhance cellular resilience.

Sarah Hatem, András K Ponti, Christopher Hine.

Fibroblast growth factor 21 (FGF21) is a stress-induced endocrine hormone that regulates metabolism. Grandl et al. show that FGF21, through its receptor β-klotho (KLB), enhances sulfide signaling and hydrogen sulfide production, strengthening the unfolded protein response and integrated stress response to promote stress resilience, metabolic adaptation, and potentially healthy aging.

DOI: https://doi.org/10.1016/j.cmet.2026.06.009
Islets. 2026 Dec 31. 18(1): 2692859

IFNα and bleomycin-induced DNA damage activate distinct stress responses in human islets and induced pluripotent stem cell-derived islet cells.

Roozbeh Akbari Motlagh, Nayara Rampazzo Morelli, Nicole Alcasid, Peter J Thompson.

  Pancreatic β-cells undergo different stress responses during the development of type 1 diabetes (T1D), such as the type I interferon (IFN) response and senescence. Although the IFN response leads to endoplasmic reticulum (ER) stress and has been linked to senescence in other cell types, the extent to which senescence and the type I IFN response are related pathways in human β-cells are unclear. To address this question, we compared the transcriptional and protein secretory responses of human donor islets and induced pluripotent stem cell-derived islet cells (SC-islet cells) to IFNα and chemically-induced DNA damage using bleomycin. While IFNα induced a classical IFN response involving HLA Class I genes, ER stress genes, and reversible chemokine secretion, it did not lead to stable induction of senescence-related genes or a senescence-associated secretory phenotype (SASP) in human islets. Similarly, in SC-islet cell models derived from two donors with different HLA haplotypes, IFNα treatment led to the upregulation of IFN genes and HLA Class I genes without an effect on senescence genes or SASP. Conversely, bleomycin-induced DNA damage in SC-islet cells led to signatures of senescence without an effect on IFN genes, ER stress genes, or HLA Class I. Taken together, these data suggest that IFNα exposure and DNA damage elicit distinct stress responses in human donor islets and SC-islet cells. These findings have implications for our understanding of heterogeneity in β-cell stress in T1D.

Keywords:  SC-islet cells; Type 1 Diabetes (T1D); pancreatic β-cell stress; senescence; type I IFN response

DOI:  https://doi.org/10.1080/19382014.2026.2692859
Aging Cell. 2026 Jul;25(7): e70620

Proteostasis Rebalancing by LET-607 Deficiency Promotes Longevity.

Haixiang Tong, Wei Li, Pangui Yuan, Feng Li, Qin Liu, Shanshan Pang, Haiqing Tang.

  Disruption of proteostasis is a hallmark of aging. Given that cellular resources are limited, this necessitates a coordinated orchestration of different proteostatic subsystems. Yet, the principles governing this process, including the potential role of trade-offs, are not well defined. Here, we report a trade-off between the endoplasmic reticulum unfolded protein response (UPRER) and the cytosolic UPR (UPRcyto) in C. elegans that influences lifespan. We find that wild-type animals maintain high UPRER activity but low UPRcyto activity, a balance actively enforced by the transcription factor LET-607 (ortholog of mammalian CREBH). Consequently, LET-607 deficiency releases this trade-off, causing a seesaw-like rebalancing: UPRER activity decreases while UPRcyto increases. Strikingly, this rebalancing contributes to longevity: animals lacking LET-607 exhibited extended lifespan in a UPRcyto dependent manner. Mechanistically, LET-607 deficiency downregulates one-carbon cycle, which provides the methyl donor S-adenosylmethionine. This subsequently alleviates H3K9me-mediated repression at the promoters of UPRcyto genes, a process involving the regulators and readers of this histone mark, leading to UPRcyto activation. Our study reveals a transcriptional mechanism that enforces a proteostatic trade-off and demonstrates that evolutionarily acquired UPR balance in wild-type animals is suboptimal for longevity, supporting the antagonistic pleiotropic theory of aging.

Keywords:  HSF‐1; longevity; proteostasis; unfolded protein response

DOI:  https://doi.org/10.1111/acel.70620
Res Sq. 2026 Jul 01. pii: rs.3.rs-10144286. [Epub ahead of print]

Mechanosensing at the endoplasmic reticulum by IRE1.

Hesso Farhan, Michaela Mayr, Luiz Garcia-Souza, Murphy McDermott, Utku Horzum, Yannick Frey, Margot Haun, Stephan Geley, Chao Jiang, Mattias Luber, Anush Bakunts, Camilla Pirolo, Alesia Yakimchyk, Klaus Liedl, Wylie Stroberg, Timo Betz, Liam Holt.

Sensing and integration of mechanical forces in eukaryotic cells have largely been attributed to the plasma membrane and the nucleus. Here, we identify the endoplasmic reticulum (ER) as an autonomous mechanosensitive organelle and uncover IRE1 as an ER-resident mechanosensor. We show that applying mechanical forces to ER membranes increases lateral tension, which is sensed by the transmembrane domain of IRE1. Mechano-activation of IRE1 was unrelated to its canonical role in the unfolded protein response and occurred independently of nuclear mechanosensing. Instead, mechanically activated IRE1 triggered JNK signaling and increased global protein synthesis independently of XBP1 splicing. In engineered skeletal muscle tissue, both electrical stimulation and passive stretch similarly activated IRE1, increased translation, and contributed to training-induced increases in contractile force. Collectively, our results uncover a non-canonical role for IRE1 as an ER-based mechanosensor that couples mechanical forces to the regulation of protein translation.

DOI: https://doi.org/10.21203/rs.3.rs-10144286/v1
BMC Cancer. 2026 Jul 04.

Machine learning-driven development of a novel unfolded protein response-related gene signature for predicting lung adenocarcinoma patient prognosis.

Rui Jiao, Chengyang Wu, Tao Zhang, Hanyu Yan, Weidong He, Zhaoyang Wang, Xiaolong Yan.

  Lung adenocarcinoma (LUAD) is the most common lung cancer histological subtype. Although the unfolded protein response (UPR) has been linked to various human diseases, its role in LUAD remains unclear. To identify UPR-related genes, we applied various methods, including weighted gene co-expression network analysis, differential expression analysis, and multivariate Cox regression. Ten machine learning algorithms were used to construct a UPR-related signature (UPRRS), which was validated using multiple public LUAD datasets. The UPRRS was integrated into a nomogram used in clinical practice for prognosis prediction. We also evaluated predicted drug sensitivity patterns across different risk subgroups. We identified 33 UPR-associated hub genes. A UPRRS was developed through systematic evaluation of 101 machine-learning combinations, exhibiting stable prognostic performance across multiple cohorts. Integration of the UPRRS into a nomogram facilitated the construction of a quantitative prognostic model. Significant differences in biological processes and tumor microenvironment immune cell infiltration were observed between the high- and low-risk UPRRS groups. All five UPRRS genes (ALDH2, FKBP4, KLF4, LAIR1, SIDT2) were validated at the protein level in LUAD cell lines, and FKBP4 was further confirmed by IHC in clinical tissues. Functional experiments showed that FKBP4 knockdown inhibited proliferation, migration, and invasion of A549 and H1975 cells, supporting a potential role for FKBP4 in LUAD progression. Our UPRRS provides a promising tool for prognostic stratification and may offer additional insights into tumor immune microenvironment characterization and therapeutic response prediction in LUAD.

Keywords:  Lung adenocarcinoma; Machine learning; Prognostic signature; Risk stratification; Unfolded protein response

DOI:  https://doi.org/10.1186/s12885-026-16477-2