bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–08–16
twelve papers selected by
Susan Logue, University of Manitoba
  1. Decoding the impact of lipid saturation on ER signaling networks, ERSU, UPR, and ERAD.
  2. Differential Effects of PERK and IRE1α Silencing on Expression of Apoptosis and Autophagy Markers in T-Lymphoblastic Leukemia MOLT-3 Cells.
  3. Targeting the unfolded protein response in cancer: mechanisms, small-molecule inhibitors, and translational challenges.
  4. The ARLA1A-NAC089 module coordinates ER phagy with the unfolded protein response to maintain cellular homeostasis in plants.
  5. Spatial and functional characterization of ER stress proteins links fibroblast plasticity and proliferative processes in human osteoarthritic synovitis.
  6. Endoplasmic reticulum stress-driven inflammatory mediators in metabolic disorders: From molecular mechanisms to targeted therapies.
  7. Chrysosplenetin-induced TMED3 aggregation triggers unfolded protein response in pancreatic cancer.
  8. Obesity-associated unfolded protein response, oxidative stress, and NRF2 signaling.
  9. Hepatocyte-intrinsic ER stress and NRF2 initiate primary sclerosing cholangitis, providing therapeutic insights.
  10. RNF5 promotes acute lung injury through HSPA5 ER-to-cytosol translocation and resultant PERK activation.
  11. USP8 controls proteostasis pathways in B cells and multiple myeloma.
  12. Complementary intra- and extracellular AGR2 activities support epithelial ovarian cancer cell aggressiveness.
  1. PLoS One. 2026 ;21(8): e0345910
    Decoding the impact of lipid saturation on ER signaling networks, ERSU, UPR, and ERAD.
    Xia Li, Maho Niwa.
      The faithful inheritance of a functional endoplasmic reticulum (ER) in Saccharomyces cerevisiae is safeguarded by the ER Stress Surveillance (ERSU) checkpoint, which delays cytokinesis when ER homeostasis is perturbed. Under stress, ER transmission to the daughter cell is halted, while in parallel-but through independent pathways-the Unfolded Protein Response (UPR) restores ER function and ER-associated degradation (ERAD) eliminates misfolded proteins, ultimately allowing cell cycle re-entry. ER stress also transiently stimulates sphingolipid biosynthesis, with the intermediate phytosphingosine (PHS) acting as a key activator of ERSU. Yet how broader lipid parameters-such as membrane composition and saturation-reshape ER quality control and, in particular, govern ER inheritance during division remains poorly understood. To begin addressing this question, a tightly controlled experimental system was employed to selectively alter lipid saturation while monitoring ER inheritance within the context of ER homeostasis maintained by the UPR and ERAD. This analysis revealed that perturbations in lipid saturation exert specific effects on ER inheritance that are distinct from their impact on UPR activation and ERAD efficiency. These findings support a central role for lipid homeostasis in ER functional regulation and suggest that membrane lipid composition contributes to the coordination of ERSU, UPR, and ERAD during ER inheritance under stress.
    DOI:  https://doi.org/10.1371/journal.pone.0345910
  2. Int J Mol Sci. 2026 Jul 24. pii: 6588. [Epub ahead of print]27(15):
    Differential Effects of PERK and IRE1α Silencing on Expression of Apoptosis and Autophagy Markers in T-Lymphoblastic Leukemia MOLT-3 Cells.
    Ekaterina Sergeevna Prokopenko, Tatyana Vladimirovna Sokolova, Olga Vladimirovna Nadei, Anastasia Dmitrievna Trubnikova, Natalia Ivanovna Agalakova.
      Cancer cells are able to survive under conditions of high endoplasmic reticulum (ER) stress by activating the adaptive unfolded protein response (UPR), which is closely linked with autophagy. On the other hand, excessive and prolonged ER stress leads to apoptosis. However, the relationships between different UPR branches and apoptosis or autophagy vary in cancer cells of different origins and depend on the extent and nature of the stress signal. This study was designed to establish the role of ER stress sensors protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1 (IRE1α) in apoptosis or autophagy signaling in T-lymphoblastic leukemia MOLT-3 cells via the RNA interference method. The cells were transfected with small interfering RNAs (si-PERK, si-IRE1α, or si-Cont) for 6 h and further cultured under normal conditions for 72 h to provide an insight into chronic effects of the gene silencing. The expression of apoptosis and autophagy effectors at the mRNA and protein levels was compared using RT-PCR and Western blot assays, respectively. Transfection of the cells with PERK siRNA led to a significant decrease in PERK protein and gene expression, and decreased phosphorylation of its downstream effector eukaryotic initiation factor 2α (eIF2α). PERK silencing was accompanied by activation of apoptosis-related genes and proteins-BCL2-associated X (Bax), caspase-3, C/EBP homologous protein (CHOP), while the levels of autophagy markers (Unc-51 like autophagy activating kinase 1 (ULK1), Beclin-1, and microtubule-associated proteins 1A/1B light chain 3 (LC3A/B)) remained stable. In contrast, treatment of the cells with si-IRE1α reduced the content of IRE1α, X-box-binding protein 1 (sXBP1), and glucose-regulated protein 78 (GRP78) proteins, but increased ERN1 gene expression. IRE1α RNA interference did not affect the levels of the pro-apoptotic marker Bax, but suppressed caspase-3, CHOP, c-Jun N-terminal kinase (JNK), and autophagy signaling molecules (ULK1, Beclin-1, LC3A/B) at both the transcriptional and translational levels. These results indicate that the PERK pathway is an important contributor to the survival of MOLT-3 cells under basal ER stress, while PERK depletion compromises the resistance of cells to UPR-mediated apoptosis. The IRE1α UPR branch is directly linked with autophagy-dependent signaling, although IRE1α knockdown exerted a more complicated influence on the cells, probably via activation of multiple pro-death and compensatory pro-survival regulatory mechanisms.
    Keywords:  IRE1α; PERK; RNA interference; T-lymphoblastic leukemia MOLT-3 cells; apoptosis; autophagy
    DOI:  https://doi.org/10.3390/ijms27156588
  3. Front Immunol. 2026 ;17 1878552
    Targeting the unfolded protein response in cancer: mechanisms, small-molecule inhibitors, and translational challenges.
    Meizhen Lin, Zhijie Li.
      Endoplasmic reticulum (ER) stress, triggered by the accumulation of misfolded proteins, activates the unfolded protein response (UPR) to restore protein homeostasis. Dysregulated ER stress responses have emerged as critical modulators of cancer progression and immune escape, influencing the initiation, development and maintenance of antitumor immunity. The UPR is mediated by three principal sensors-PERK, IRE1α, and ATF6-each operating at distinct regulatory levels to coordinate translational reprogramming, RNA processing, and transcriptional reprogramming. Through these mechanisms, ER stress promotes malignant progression, tumor growth, and metastasis, while excessive activation can instead trigger cell death. Given this context-dependent duality, pharmacological targeting of the UPR has emerged as a promising anticancer strategy. For instance, IRE1α inhibitors block XBP1 splicing and RIDD-mediated immune escape, PERK inhibitors and ISR modulators reverse chemoresistance, ATF6-targeted strategies modulate ATF6-dependent tumor growth and treatment responses, and chemical chaperones exhibit both cytoprotective and antitumor effects depending on tumor context. This review integrates recent mechanistic insights into UPR-driven tumor progression, including pathway crosstalk, immune regulation, and immunotherapy resistance, with advances in small-molecule inhibitors, while critically evaluating their therapeutic potential and translational challenges in cancer treatment.
    Keywords:  ATF6; IRE1α; PERK; cancer therapy; chemical chaperones; unfolded protein response
    DOI:  https://doi.org/10.3389/fimmu.2026.1878552
  4. Dev Cell. 2026 Aug 04. pii: S1534-5807(26)00276-5. [Epub ahead of print]
    The ARLA1A-NAC089 module coordinates ER phagy with the unfolded protein response to maintain cellular homeostasis in plants.
    Lianming Yang, Weixin Luo, Tingting Huang, Shuo Wang, Zhiran Cao, Dong Jiang, Lei Pang, Jian-Xiang Liu, Sicong He, Ruixi Li.
      The endoplasmic reticulum (ER) is a critical quality-control organelle for protein homeostasis within the cell. The accumulation of misfolded or unfolded proteins triggers ER stress, which can be alleviated through the unfolded protein response (UPR) and ER phagy. These processes work in concert to preserve ER homeostasis, yet the molecular interactions between them remain poorly understood in plants. In this study, we identify the ER-anchored transcription factor NAC089 as an ER-phagy receptor acting downstream of the ADP-ribosylation factor (ARF)-like (ARL) GTPase ARLA1A under carbon starvation. Furthermore, we demonstrate that active ARLA1A inhibits ER phagy by negatively regulating NAC089. Notably, the ARLA1A-NAC089 axis coordinates ER phagy with the UPR to balance cell survival and death. Our findings unveil a multi-layered regulatory network that is essential for maintaining cellular homeostasis and enhancing plant adaptation to environmental stresses.
    Keywords:  ARLA1A; ER phagy; ER stress; NAC089; UPR
    DOI:  https://doi.org/10.1016/j.devcel.2026.07.007
  5. Cell Death Differ. 2026 Aug 12.
    Spatial and functional characterization of ER stress proteins links fibroblast plasticity and proliferative processes in human osteoarthritic synovitis.
    Zoé Gendebien, Christophe Poulet, Céline Deroyer, Geneviève Paulissen, Pauline Salpetier, Alexandre Hego, Gaëtan Lefèvre, Gaël Cobraiville, Sophie Neuville, Zelda Plener, Christophe Daniel, Thierry Thirion, Tatiana Sokolova, Patrick Durez, Patrice Hemon, Yuna Delarue, Nadège Marec, Elettra Bianchi, Philippe Delvenne, Clio Ribbens, Dominique de Seny.
      A strong crosstalk exists between endoplasmic reticulum (ER) stress and synovitis. Beyond their canonical role in protein folding, ER stress chaperones may promote inflammation, cell survival, and fibroblast activation under pathological conditions. This study aimed at localizing and quantifying 11 ER stress proteins (BiP, HYOU1, MANF, PDIA4, GANAB, HSP90B1, TXNDC5, DNAJB11, LMAN1, ERP29, CALR) in human inflamed synovial membranes and at investigating their expression in fibroblast-like synoviocytes (FLS) under ER stress, pro-inflammatory, or pro-fibrotic stimuli. By immunohistochemistry, on a first cohort of formalin-fixed paraffin-embedded (FFPE) biopsies obtained from patients with osteoarthritis (OA), chronic pyrophosphate arthropathy (CPPA), and rheumatoid arthritis (RA), these ER chaperones were primarily localized to the lining in low-grade inflammation (Tak <4) and expanded to the sublining under high inflammatory conditions (Tak ≥4), with a widespread distribution in RA. Imaging mass cytometry, applied to a second cohort of FFPE tissue samples collected from patients diagnosed with OA and RA, revealed the co-expression of ER stress proteins with CD55⁺ FLS in the lining and their progressive infiltration into the sublining along with CD34⁺CD31- FLS during inflammation. These observations were confirmed by immunofluorescence on a larger cohort of OA patients. As inflammation progresses, there is a loss of co-expression with CD55 in the lining, accompanied by a gradual shift towards co-expression with CD34 in the sublining. In vitro, ER stress proteins, particularly BiP, HYOU1, MANF, PDIA4, HSP90B1, LMAN1, CALR, and DNAJB11 are overexpressed in human OA FLS following ER stress, pro-inflammatory or pro-fibrotic stimulation, with BiP, PDIA4, HSP90B1, ERP29, and CALR also being secreted. PDIA4 emerged as a central player: its depletion significantly impaired FLS proliferation and migration, highlighting a direct role in driving synovitis. This study provides the first spatial and functional characterization of ER chaperones in human arthritic synovium, linking ER stress to fibroblast plasticity, inflammation, and fibrosis.
    DOI:  https://doi.org/10.1038/s41418-026-01841-3
  6. Pharmacol Res. 2026 Aug 11. pii: S1043-6618(26)00289-6. [Epub ahead of print]231 108374
    Endoplasmic reticulum stress-driven inflammatory mediators in metabolic disorders: From molecular mechanisms to targeted therapies.
    Bo Wen, Xiaojin Wu, Kaiying Zhang, Hao Cui, Dandan Ma.
      Nutrient overload induces a state of chronic, low-grade inflammation termed metaflammation, which contributes to the development of metabolic disorders, such as type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD). As a nutrient-sensitive organelle, the endoplasmic reticulum (ER) is highly vulnerable to systemic metabolic burden. When its adaptive capacity is exceeded, ER stress (ERS) activates the unfolded protein response (UPR) and drives cellular dysfunction. This review delineates how the canonical UPR sensors transduce metabolic stress into pro-inflammatory signaling cascades. By engaging key transcriptional regulators and inflammasome complexes, these pathways drive the production of inflammatory mediators, including cytokines, chemokines, and bioactive lipids, such as leukotrienes (LTs) and prostaglandins. Subsequently, the review discusses the organ-specific consequences of ERS in the liver, pancreas, adipose tissue, vascular endothelium, and hypothalamus, highlighting how this stress sustains a self-reinforcing cycle of tissue injury and metabolic dysfunction. Emerging therapeutic strategies are also summarized, ranging from broad-spectrum chemical chaperones to precision UPR modulators and organ-targeted delivery systems aimed at disrupting this pathogenic axis and restoring metabolic homeostasis.
    Keywords:  Bioactive lipids; Endoplasmic reticulum stress; Immunometabolism; Metaflammation; Targeted therapy; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.phrs.2026.108374
  7. EMBO Mol Med. 2026 Aug 13.
    Chrysosplenetin-induced TMED3 aggregation triggers unfolded protein response in pancreatic cancer.
    Zhe Zhang, Ningna Weng, Xuanhao Gu, Yi Zang, Qitai Chen, Rujia Zheng, Xishan Yang, Gubu Amu, Danyang Zhao, Zhihao Ma, Jinyan Huang, Tingbo Liang, Qi Zhang.
      Pancreatic cancer (PC) continues to demand urgent therapeutic innovation given its limited treatment options. Here, through phenotypic screening of a natural product library followed by systematic validation, we identified chrysosplenetin (CHR) as a bioactive compound with anti-PC activity. Transcriptomic profiling and functional analyses demonstrated that CHR induced endoplasmic reticulum (ER) stress, thereby activating the unfolded protein response (UPR) and subsequent apoptosis, while paradoxically triggering a protective autophagy. Genetic or pharmacological inhibition of autophagy potentiated CHR-induced antitumor efficacy. Using an integrated approach including proteomic analysis, bio-layer interferometry, cellular thermal shift assay, and molecular docking, we confirmed TMED3 as a direct target of CHR. Functional studies revealed that disruption of TMED3 expression partially restored ER homeostasis, attenuating CHR-induced UPR activation and apoptosis. Furthermore, CHR combined with standard chemotherapy or autophagy inhibitors exhibited enhanced antitumor activity in preclinical models, providing a basis for future therapeutic exploration of the TMED3-ER stress axis. Together, our findings establish TMED3 as a novel therapeutic target in PC, revealing that disrupting ER proteostasis via TMED3 perturbation represents a potential therapeutic strategy warranting further investigation.
    DOI:  https://doi.org/10.1038/s44321-026-00506-5
  8. Int J Obes (Lond). 2026 Aug 13.
    Obesity-associated unfolded protein response, oxidative stress, and NRF2 signaling.
    Şeyma Özgür, Alessandro Medoro, Sergio Davinelli, Nicole Bender, Luciano Saso, Pelin Telkoparan-Akillilar.
      Obesity has become a major global health problem. It is characterized by increased body fat storage and is associated with excessive food intake. Although obesity is often thought of as a simple problem involving fat accumulation in the body, it is a complex disease that alters cellular defense systems and causes low-grade chronic inflammation, which can contribute metabolic syndrome. Even though obesity is an inflammatory disease, an increase in the formation of reactive oxygen species (ROS) is also observed due to excess nutrition. Excessive ROS production contributes to obesity progression and endoplasmic reticulum (ER) stress. In response to oxidative stress, cells activate antioxidant defense mechanisms either through unfolded protein response (UPR) pathways or via UPR-independent signaling pathways. Nuclear factor-erythroid 2-related factor-2 (NRF2) controls the transcription of multiple genes encoding antioxidant and cytoprotective proteins. NRF2 is of interest in obesity research as it can be activated with or without UPR elements and plays a role in the regulation of antioxidant response. Targeting NRF2 through multiple approaches has been shown to reduce or prevent obesity and obesity associated metabolic complications. This review examines the molecular mechanisms of NRF2 activation in obesity, with particular focus on its bidirectional crosstalk with the UPR and discusses the therapeutic implications of targeting this axis in obesity and its related metabolic dysfunction.
    DOI:  https://doi.org/10.1038/s41366-026-02188-y
  9. Proc Natl Acad Sci U S A. 2026 08 18. 123(33): e2616211123
    Hepatocyte-intrinsic ER stress and NRF2 initiate primary sclerosing cholangitis, providing therapeutic insights.
    Lianyuan Tao, Peng He, Jiachen Ge, Qifei Guan, Erpei Wang, Ipsita Mohanty, Cristina Bez, Won-Suk Song, Ling Lan, Jingjing Qi, Yueqi Zhang, Peng Zhang, Yuxiao Liu, Avinash Mukkala, Yechen Feng, Mandy Zhu, Qiong Zhou, Tingting Ai, Kosuke Watari, Laura Antonucci, Li Gu, Li Huang, Tao Qin, Deyu Li, Dianrong Xiu, Cholsoon Jang, Judith A Varner, Pieter C Dorrestein, Beicheng Sun, Michael Karin.
      primary sclerosing cholangitis (PSC) is a severe liver disease that can progress to cholangiocarcinoma. Therapeutic development has been hindered by the rarity of PSC and by its poorly understood origin, which reflects incompletely defined genetic and environmental risk factors. Here we describe a mouse model that combines two suspected environmental risk factors, hepatocyte-intrinsic ER stress and oxidative stress, which leads to activation of transcription factor NRF2 in both hepatocytes and cholangiocytes. Genetically affected mice, as well as mice treated with an ER stress inducer and an NRF2 activator, progressed to PSC with human-like features. Specifically, hepatocyte-intrinsic ER stress in cooperation with activated NRF2 leads to indirect activation of JNK-JUN signaling, which abrogates HNF1α-stimulated Fxr gene transcription and reduces expression of the bile salt export pump BSEP. These signaling abnormalities, whose clinical relevance is supported by single cell transcriptomics of human PSC tissue, cause cholestasis, hepatocyte and bile canaliculi injury, biliary hyperplasia, and periductular fibrosis, which define PSC. Congruently, alleviation of cholestasis and/or inhibition of biliary hyperplasia resolve PSC in mice.
    Keywords:  ER stress; NRF2; cholestasis; primary sclerosing cholangitis
    DOI:  https://doi.org/10.1073/pnas.2616211123
  10. Cell Death Differ. 2026 Aug 10.
    RNF5 promotes acute lung injury through HSPA5 ER-to-cytosol translocation and resultant PERK activation.
    Ya-Zhou Sun, Xin-Yan Li, Jia Wang, Meng-Liu Zeng, Wei-Yi Qu, Xu Cheng, Lei Luo, Wei Wang, Juan Yang, Jun Zhang, Han Tian, Peng Zhang, Zhi-Gang She, Hongliang Li, Xiao-Jing Zhang.
      Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe conditions lacking specific pharmacological treatments. Endoplasmic reticulum (ER) stress plays a pivotal role in their pathophysiology, yet the precise regulatory mechanisms remain elusive. In this study, we identify the E3 ubiquitin ligase ring finger protein 5 (RNF5) as a critical driver of ALI/ARDS. RNF5 is markedly upregulated in response to ALI and significantly exacerbates lung injury by stabilizing HSPA5 (heat shock protein family A member 5), a master regulator of the unfolded protein response (UPR). Notably, in vivo Rnf5 ablation effectively attenuated pulmonary edema, inflammatory cell infiltration, and apoptosis, whereas lung-specific Rnf5 overexpression worsened inflammation and cell death in mice. Mechanistically, RNF5 interacts with HSPA5 and competitively blocks its binding to PERK, facilitating PERK release. Furthermore, RNF5 promotes the retro-translocation of HSPA5 from the ER lumen to the cytosol. In the cytosol, RNF5 mediates the K6- and K63-linked polyubiquitination of HSPA5, enhancing its thermal stability and preventing its re-entry into the ER. This spatial sequestration sustains the persistent dissociation of the PERK-HSPA5 complex, leading to the hyperactivation of the pro-apoptotic and pro-inflammatory PERK-eIF2α-CHOP signaling cascade. The ability of RNF5 to promote ALI is strictly dependent on its E3 ligase activity. In conclusion, our findings uncover a compartment-specific regulatory mechanism of HSPA5, suggesting that the RNF5-HSPA5-PERK axis represents a promising therapeutic target for ALI/ARDS.
    DOI:  https://doi.org/10.1038/s41418-026-01843-1
  11. Leukemia. 2026 Aug 11.
    USP8 controls proteostasis pathways in B cells and multiple myeloma.
    Almut Dufner, Fabien Thery, Gianni Monaco, Jelena Lazarevic, Oliver Gorka, Nina Chevalier, Marta Campos Alonso, Maximilian Frosch, Gerbrand J van der Heden van Noort, Kira Allmeroth, Marco Prinz, Olaf Groß, Huib Ovaa, Paul P Geurink, Wolfgang W Schamel, Martin S Denzel, Vigo Heissmeyer, Benedikt Jacobs, Mirle Schemionek, Francis Impens, Heiko Bruns, Klaus-Peter Knobeloch.
      Ubiquitin-specific protease 8 (USP8) plays a pivotal role in the regulation of endosomal and lysosomal trafficking and is critically involved in the pathogenesis of various tumor entities. USP8 represents a vulnerability gene in multiple myeloma (MM), suggesting a functional role in the B- and plasma cell compartment. Here we analyzed mice with stage-specific Usp8 deletion during B-cell development and investigated its role in patient-derived MM cells that are sensitive or resistant to the proteasome inhibitor Bortezomib (BTZ) using USP8 depletion and treatment with DUB-IN-2, a reported USP8 inhibitor. Usp8 depletion in Usp8f/fCd19-Cre mice affected B-cell survival and development favoring immature, innate-like B cells, and germinal center and plasma cells, while also elevating immune-responses and causing Roquin depletion. Cells expressing catalytically inactive USP8 accumulated proteins modified with mixed ubiquitin/NEDD8 chains indicative of proteotoxic stress, which we identified as preferred USP8 substrates. In MM cells, USP8 knockdown reduced survival via lysosomal dysfunction. In contrast, DUB-IN-2 induced an enhanced ER stress response to treatment with BTZ questioning DUB-IN-2 function as a USP8 inhibitor, as confirmed by biochemical analysis. Thus, our results highlight the therapeutic potential of targeting USP8 and identify the combination of DUB-IN-2 and BTZ as a novel strategy for treating BTZ-resistant MM.
    DOI:  https://doi.org/10.1038/s41375-026-03086-y
  12. Oncogene. 2026 Aug 10.
    Complementary intra- and extracellular AGR2 activities support epithelial ovarian cancer cell aggressiveness.
    Marianne Guilbard, Saïd Taouji, Marc Aubry, Jacques Robert, Raphael Pineau, Valérie Velasco, Romane Florent, Louis-Bastien Weiswald, Cecile Hartog, Coriolan Lebreton, Alix Coulon, Sabrina Croce, Guillaume Babin, Cédric Chaveroux, Stéphanie Beq, Eric Chevet, Delphine Fessart, Frédéric Delom.
      Anterior Gradient 2 (AGR2) is an endoplasmic reticulum (ER)-resident protein that belongs to the protein disulphide isomerase (PDI) family, and whose expression and secretion are induced by stress. Extracellular (secreted) AGR2 has been proposed as a marker of ER stress-related proteostasis alterations. Cancer cells frequently overexpress intracellular AGR2 (iAGR2) and secrete extracellular AGR2 (eAGR2). These features are associated with tumour progression and may serve as potential biomarkers in epithelial ovarian cancer (EOC). To investigate the roles of both iAGR2 and eAGR2 in EOC, we first generated EOC cells overexpressing iAGR2 and secreting eAGR2. Antibodies blocking eAGR2 reduced the proliferation and migration of these overexpressing cells. Concurrently, supplementation of parental cells with recombinant eAGR2 partially rescued these properties, further supporting a functional extracellular role for AGR2 in EOC. Quantitative proteomics, complemented by analysis of the TCGA database, revealed that eAGR2 modulated the expression of proteins involved in autophagy. This suggests that eAGR2-induced signalling may enhance catabolic activity under stress conditions, thereby increasing nutrient availability and, in turn, facilitating protein synthesis. This was reflected in the increased translational activity observed in AGR2-overexpressing and eAGR2-stimulated cells. Our results highlight two distinct, compartmentalised roles for AGR2. Specifically, iAGR2 acts as an ER-resident PDI, enhancing protein folding and ER quality control. In a complementary manner, eAGR2 functions as a metabolic regulator that may relieve constraints on tumour cell aggressiveness by maintaining autophagic flux and promoting protein synthesis. Overall, these findings support a dual-compartment model in which iAGR2 couples ER proteostasis with the metabolic and translational stimulation mediated by eAGR2.
    DOI:  https://doi.org/10.1038/s41388-026-03938-y
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