bims-unfpre 2026-06-07 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–06–07
eight papers selected by
Susan Logue, University of Manitoba

Endoplasmic Reticulum Stress as a Stage-Dependent Regulatory Hub in Rheumatoid Arthritis.
CD36 exacerbates obesity-related vascular damage by promoting ER stress and endothelial insulin signaling impairment.
The OAS1-FASN axis promotes pancreatic cancer by coordinating lipogenic stress and the unfolded protein response.
miR-489 induces immunogenic cell death in breast cancer by targeting LAPTM4B.
Fasting disrupts the InsP₆-HDAC3 axis to drive ER stress-mediated clearance of DNA-damaged cells and enforce tissue quality control.
Cell surface GRP78 and the UPR pathway as novel promising therapeutic targets in cancer: an insight into the treatment of acute leukemia by using GRP78-CART cells.
Coordinated expression and assembly of BiP, p58IPK, and ER chaperone complexes maximize proinsulin folding in pancreatic β cells.
The mannosyltransferase DPM1 regulates the activity of ER-stress sensor IRE1 in colorectal cancer.

J Inflamm Res. 2026 ;19 606604

Endoplasmic Reticulum Stress as a Stage-Dependent Regulatory Hub in Rheumatoid Arthritis.

Na Hu, Yaguang Song, Ting Yu, Hongbo Li, Xin Wang, Qingguo Lv.

  Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Beyond its canonical role in maintaining proteostasis, growing evidence indicates that endoplasmic reticulum (ER) stress acts as a dynamic regulatory hub integrating inflammatory signaling, metabolic reprogramming, and cell fate control within the RA synovium. Activation of the unfolded protein response (UPR) sensors-IRE1α, PERK, and ATF6-initially promotes adaptive compensation aimed at restoring ER homeostasis. However, sustained or maladaptive signaling drives inflammatory amplification, apoptosis resistance in fibroblast-like synoviocytes (FLS), immune dysregulation, and enhanced osteoclastogenesis. Recent studies further reveal stage-dependent and cell type-specific patterns of ER stress activation, underscoring its context-dependent pathogenic functions during disease initiation and progression. Accordingly, therapeutic strategies are shifting from broad suppression of ER stress toward precision modulation of discrete UPR modules, including alleviation of excessive proteostatic burden and selective induction of pro-apoptotic signaling in pathogenic synoviocytes. By integrating mechanistic insights with translational perspectives, this review highlights ER stress as a context-dependent signaling network and a potential precision therapeutic target in RA.

Keywords:  endoplasmic reticulum stress; fibroblast-like synoviocytes; rheumatoid arthritis; unfolded protein response

DOI:  https://doi.org/10.2147/JIR.S606604
Cell Signal. 2026 Jun 03. pii: S0898-6568(26)00296-2. [Epub ahead of print] 112643

CD36 exacerbates obesity-related vascular damage by promoting ER stress and endothelial insulin signaling impairment.

Qian Xu, Yufan Gu, Kunping Zhuo, Yaqian Sun, Yue Ma, Yuliang Zhang, Yanru Zhen, Rong Li, Lu Zhang, Yang Yao, Hui Jia, Yueyang Liu, Ming-Sheng Zhou.

  Obesity-associated elevated plasma free fatty acids (FFAs) levels contribute to vascular injury and insulin resistance, but the role of CD36remains incompletely understood. This study investigated the role of CD36 in regulating high-fat diet (HFD)-induced metabolic disturbances and vascular dysfunction and its downstream signaling. In HFD-fed mice, CD36 knockdown lowered body weight, abdominal fat accumulation, and serum lipid profile without affecting blood glucose. Moreover, CD36 knockdown reversed HFD-induced increases in aortic reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress. It also attenuated aortic wall thickening, fibrosis, and impaired endothelial-dependent vasorelaxation to insulin. In palmitic acid (PA)-treated human umbilical vein endothelial cells, CD36 silencing similarly alleviated PA-induced ROS production, ER stress, and increased expression of pro-inflammatory proteins, while restoring impaired insulin-stimulated AKT/eNOS phosphorylation. Mechanistically, the mitochondrial-targeted antioxidant MitoTEMPO attenuated PA-induced ROS generation, ER stress, and rescued insulin signaling, indicating mitochondrial ROS as an upstream mediator. Conversely, CD36 overexpression exacerbated PA-induced ROS production, ER stress, and insulin signaling impairment, all of which were reversed by the antioxidant NAC or the ER stress inhibitor TUDCA. These gain- and loss-of-function experiments establish CD36 as a critical upstream regulator coupling PA stimulation to mitochondrial ROS and subsequent ER stress. Notably, as systemic CD36 knockdown was used in vivo, the potential contribution of vascular smooth muscle CD36 cannot be excluded. In conclusion, CD36 aggravates obesity-related vascular injury by promoting ROS-dependent ER stress, leading to endothelial insulin signaling impairment. Targeting CD36 or its downstream oxidative/ER stress pathways may represent a promising therapeutic strategy for obesity-associated vascular complications.

Keywords:  CD36; ER stress; Endothelial insulin signaling; Obesity; Oxidative stress; Palmitic acid

DOI:  https://doi.org/10.1016/j.cellsig.2026.112643
Cell Death Dis. 2026 Jun 03.

The OAS1-FASN axis promotes pancreatic cancer by coordinating lipogenic stress and the unfolded protein response.

Yuheng Zhu, Hongfei Yao, Chunjing Li, Jie Peng, Jieqiong Ge, Meng Liu, Tongyi Zhang, Zhiwei Cai, Chongyi Jiang.

Metabolic reprogramming, characterized by dysregulated lipid metabolism and consequent endoplasmic reticulum (ER) stress, constitutes a hallmark of pancreatic ductal adenocarcinoma (PDAC). Within this metabolic landscape, the 2'-5'-Oligoadenylate Synthetase (OAS) family member OAS1 is identified as a critical driver of malignancy, exhibiting specific upregulation in PDAC tissues that correlates with poor patient prognosis. Functionally, OAS1 drives tumor progression, including cell proliferation and metastasis, by operating as a non-canonical metabolic regulator. Mechanistically, OAS1 binds to fatty acid synthase (FASN), maintaining its functional protein levels and thereby promoting FASN-dependent lipid synthesis. The resulting surge in de novo lipid synthesis and lipid droplet accumulation precipitates an adaptive ER stress response via the PERK-ATF4 signaling axis. Consequently, a functional OAS1-FASN axis operates to coordinate lipid overload with pro-survival ER stress signaling, establishing OAS1 as a pivotal metabolic regulator and a viable biomarker in PDAC.

DOI: https://doi.org/10.1038/s41419-026-08922-8
Front Oncol. 2026 ;16 1832140

miR-489 induces immunogenic cell death in breast cancer by targeting LAPTM4B.

Gourab Gupta, Ryan Titus, Sydney Shaw, Neha Adusumilli, Yogin Patel, Hexin Chen.

   Introduction: MicroRNA dysregulation plays a critical role in breast cancer progression, yet the functional significance of many microRNAs in tumor biology and antitumor immunity remains incompletely understood. Here, we investigated the expression pattern, clinical relevance, and biological function of miR-489 in breast cancer.
Methods: miR-489 expression was analyzed in breast cancer tissues, including basal-like/triple-negative breast cancer (TNBC) cohorts, and correlated with patient survival outcomes. Functional assays were performed in TNBC cell lines following miR-489 restoration to assess effects on cell proliferation, colony formation, and endoplasmic reticulum (ER) stress signaling. Markers of immunogenic cell death, including calreticulin exposure, ATP release, and macrophage-mediated phagocytosis, were evaluated. Mechanistic studies identified and validated target genes using molecular and functional rescue approaches.
Results: miR-489 expression was significantly reduced in breast tumors, particularly in the basal-like/TNBC subtype. Higher miR-489 levels were associated with improved patient survival across independent cohorts. Restoration of miR-489 inhibited proliferation and colony formation in TNBC cells and activated ER stress signaling. miR-489 overexpression also induced features of immunogenic cell death, including increased calreticulin surface exposure, ATP release, and enhanced macrophage phagocytosis. Lysosomal-associated protein transmembrane 4 beta (LAPTM4B) was identified as a direct functional target of miR-489. Suppression of LAPTM4B was required for miR-489-mediated ER stress activation and immunogenic cell death-like responses, while LAPTM4B overexpression partially reversed these effects.
Conclusions: Our findings identify a novel miR-489-LAPTM4B regulatory axis that links tumor suppression with immunogenic cell death in breast cancer. This pathway may represent a potential therapeutic target for improving treatment strategies, particularly in TNBC.

Keywords:  ER stress; Immunogenic cell death; breast cancer; microRNA; phagocytosis

DOI:  https://doi.org/10.3389/fonc.2026.1832140
bioRxiv. 2026 May 27. pii: 2026.05.24.727426. [Epub ahead of print]

Fasting disrupts the InsP₆-HDAC3 axis to drive ER stress-mediated clearance of DNA-damaged cells and enforce tissue quality control.

Sujan Chetterjee, Zachary Sin, Richard A Van, Nguyen Tran, Tam Tran, Anuj Shukla, Lucile Marie-Paule Jeusset, George Koshkaryan, Kevin Saldana, Rayan Muneer, Loretta Viera Preval, Lingkun Gu, Faizan Bhat, Kevin Ritter, Katherine Huang, Kayci Huff-Hardy, Richard Rood, Anas Gremida, Martin Gregory, Chien Huan Chen, Mo Weng, Frank J Dekker, Parakkal Deepak, Henning J Jessen, Kirk James McManus, Mira V Han, Prasun Guha.

Fasting drives metabolic adaptation but also elicits acute cellular stress. How this stress shapes tissue integrity is unknown. Here, we show that in the intestine, fasting depletes growth factor signaling, which triggers cellular stress. This response functions as a tissue quality-control checkpoint that selectively eliminates pre-existing DNA-damaged cells while sparing healthy counterparts. A short-term fast diminishes TGF-β signaling and elicits endoplasmic reticulum (ER) stress, driving DNA-damaged intestinal cells beyond an apoptotic threshold, thereby reducing the inflammatory burden. Mechanistically, loss of TGF-β signaling triggers FBXO22-Cullin1-mediated degradation of the inositol kinase IPMK, leading to depletion of inositol hexaphosphate (InsP₆). InsP₆ loss attenuates HDAC3 activity and initiates coordinated epigenetic and post-translational reprogramming, thereby increasing CDK5RAP3 abundance. Elevated CDK5RAP3 inhibits ribosomal RPL26 UFMylation, thereby amplifying ER stress and selectively licensing apoptosis in DNA-damaged cells. Collectively, fasting disrupts a TGF-β-InsP 6 -HDAC3 axis to drive ER stress-dependent clearance of DNA-damaged cells, enforcing tissue quality control.

DOI: https://doi.org/10.64898/2026.05.24.727426
Clin Transl Oncol. 2026 Jun 05.

Cell surface GRP78 and the UPR pathway as novel promising therapeutic targets in cancer: an insight into the treatment of acute leukemia by using GRP78-CART cells.

Nadia Giovanna Román-Anguiano, Paola Andrea Gutiérrez-Muñoz, Tania Angeles-Floriano, Nancy Lucero Martínez-Rodríguez, Laila Gutiérrez-Kobeh, Maria C Jimenez-Martinez, Ricardo Valle-Rios.

  Around 70s decade, the discovery of endoplasmic reticulum (ER) chaperones as central regulators of protein folding and quality control set a new paradigm for the understanding of cellular homeostasis. With the arrival of global proteomic approaches, several ER chaperones, including the 78-kDa glucose-regulated protein (GRP78), were unexpectedly found at the cell surface of cancer cells, linking activation of the unfolded protein response (UPR) to tumor biology. Current knowledge suggests that cell surface GRP78 (csGRP78) is a promising therapeutic biomarker, as it is virtually absent on normal cells but enriched on multiple cancers, particularly leukemias. This review summarizes the roles of the three main UPR regulators-IRE1, ATF6, and PERK-and their crosstalk with csGRP78 in leukemia, emphasizing how this network can promote survival or apoptosis. Finally, recent preclinical studies using GRP78-directed CAR-T cells are discussed, highlighting csGRP78 and the UPR pathway as attractive targets for leukemia immunotherapy.

Keywords:  Acute lymphoblastic leukemia; CART cells; GRP78

DOI:  https://doi.org/10.1007/s12094-026-04413-6
Proc Natl Acad Sci U S A. 2026 Jun 09. 123(23): e2533617123

Coordinated expression and assembly of BiP, p58IPK, and ER chaperone complexes maximize proinsulin folding in pancreatic β cells.

Insook Jang, Alec Duffey, Pamela Itkin-Ansari, Peter Arvan, Randal J Kaufman.

  Proper proinsulin folding in the endoplasmic reticulum (ER) is prerequisite to producing bioactive insulin, and proinsulin misfolding causing β cell ER stress accompanies pancreatic β cell dysfunction in type 2 diabetes (T2D). How (and which) ER chaperones coordinate to prevent proinsulin misfolding is largely unknown other than an unspecified dependence on the hsp70 member, BiP. A genetically engineered mouse enables efficient, specific pulldown of endogenous islet β cell BiP (GRP78, the major HSP70 ER chaperone) in complexes with client proteins. We demonstrate that BiP assembles in various protein complexes (including cochaperones p58IPK, GRP170, ERdj3, and oxidoreductases PDIA1 and PDIA6) that specifically bind to nonnative proinsulin. BiP requires p58IPK for productive proinsulin folding, whereas nonstoichiometric BiP excess actually hinders proinsulin folding. Coordinated and dyscoordinated BiP/cochaperone assembly in response to demand for proinsulin highlights physiologic and pathophysiologic conditions, respectively, offering a potential check point for therapeutic intervention.

Keywords:  chaperones; endoplasmic reticulum; proinsulin folding; type 2 diabetes; β cell function

DOI:  https://doi.org/10.1073/pnas.2533617123
Nat Commun. 2026 Jun 03.

The mannosyltransferase DPM1 regulates the activity of ER-stress sensor IRE1 in colorectal cancer.

Hussein Issaoui, Lina Zawil, Lola Bellone, Diogo Goncalves, Rachel Paul, Léa Di Mascio, Sonia Núñez-Vázquez, Sandrine Marchetti, Johanna Chiche, Nicolas Nottet, Simon Le Goupil, Hadrien Laprade, Lucile Bansard, Yourae Hong, Rebecca Wall, Sabine Tejpar, Caroline Truntzer, François Ghiringhelli, Suresh Poudel, Helen M Beere, Douglas R Green, Julie Pannequin, Eric Chevet, Jean-Ehrland Ricci.

Most colorectal cancer (CRC) patients exhibit resistance to immune checkpoint blockade (ICB), limiting treatment efficacy. Activating the unfolded protein response sensor IRE1α in cancer cells can induce anticancer immune responses, yet its regulation remains unclear. Here we identify Dolichyl-Phosphate Mannosyltransferase 1 (DPM1) as a regulator of IRE1 expression and activity using BioID screen. Analysis of CRC patient RNA-sequencing data reveals that low DPM1 expression correlates with an IRE1-dependent transcriptional signature, increased immune infiltration, and improved ICB responses. Mechanistically, DPM1 ablation reduces protein glycosylation, causing chronic IRE1 activation in cancer cells and enhanced cytotoxic T cell-mediated immunosurveillance. Inhibition or knock-out of IRE1 reverses this effect. These findings establish DPM1 as a modulator of IRE1 activity that influences tumor immunogenicity, suggesting its potential as a therapeutic target to improve cancer immunotherapy outcomes.

DOI: https://doi.org/10.1038/s41467-026-73942-z