bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–03–15
twelve papers selected by
Susan Logue, University of Manitoba
  1. Paneth cell SIRT1 deficiency increases intestinal stress resistance by modulating the gut microbiota.
  2. Interplay between ER stress and DNA repair pathways in solid tumors under hypoxia.
  3. ER Proteotoxic Stress Drives Mitochondrial Dysfunction in Heat-Stressed Intestinal Epithelial Cells.
  4. Weight Loss During Obesity Provokes Asparaginase-Associated Liver Steatosis and Endoplasmic Reticulum Stress.
  5. D-allose suppresses colitis associated carcinogenesis by reversing ER stress in macrophages and inhibiting cancer cell proliferation.
  6. Chemical modulation of the unfolded protein response reveals an antiviral role for the PERK pathway in human coronavirus 229E infection.
  7. S-nitrosylation contributes to ER stress and aggresome formation in Secosterol-B-mediated endothelial dysfunction.
  8. Ubiquitin-specific peptidase-19 links TDP-43 aggregation to ER stress.
  9. Small molecule screening identifies cytotoxic endoplasmic reticulum-associated degradation inhibitors in multiple myeloma.
  10. Crosstalk Between Autophagy and Paraptosis: A New Frontier in Cancer Therapy.
  11. Hypothalamic endoplasmic reticulum stress drives pubertal precocity due to early-onset obesity in female rodents.
  12. IRE1α regulates macrophage phagocytosis in immune thrombocytopenia through NR1D1 mRNA decay and lysosomal biogenesis.
  1. EMBO Rep. 2026 Mar 13.
    Paneth cell SIRT1 deficiency increases intestinal stress resistance by modulating the gut microbiota.
    Liz M Garcia-Peterson, Alicia S Wellman, Xiaojiang Xu, Ming Ji, Caroline Duval, Igor Shats, Xiaoyue Wu, Thomas A Randall, Hamed Bostan, David Cunefare, Charan K Ganta, Maria Sifre, Xin Xu, Richard S Blumberg, Jian-Liang Li, Xiaoling Li.
      Paneth cells, intestine-originated innate immune-like cells, are important for maintenance of the intestinal stem cell niche, gut microbiota, and gastrointestinal barrier. Dysfunctional Paneth cells under pathological conditions are a site of origin for intestinal inflammation. However, mechanisms underlying stress-induced Paneth cell dysregulation remain unclear. Here, we report that SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase and a well-known genetic repressor of inflammation, cell-autonomously suppresses Paneth cell function and sensitizes the gut epithelium to environmental stress. Specifically, deletion of Paneth cell SIRT1 in mice elevates Wnt signaling and ATF4/endoplasmic reticulum stress pathway in Paneth cells. These molecular alterations are coupled with increased Paneth cell abundance and enhanced anti-microbial peptide production in young mice, improved protection against intestinal immune cell expansion in aged mice, and increased resistance to chemically induced colitis. Using microbiota-depleted mice with or without fecal transplantation, we further demonstrate that Paneth cell SIRT1 deficiency ameliorates colitis by interacting with the gut microbiota. Collectively, our findings uncover an unanticipated function of Paneth cell SIRT1 in conferring stress sensitivity in the gut epithelium.
    Keywords:  Anti-microbial Peptides; ER Stress; Gut Microbiota; SIRT1; Wnt/β-catenin
    DOI:  https://doi.org/10.1038/s44319-026-00726-3
  2. Int J Cancer. 2026 Mar 09.
    Interplay between ER stress and DNA repair pathways in solid tumors under hypoxia.
    Aastha Jadhav, Neeru Singh.
      Solid tumors often develop a hypoxic microenvironment that triggers adaptive cellular responses, promoting tumor progression, aggressiveness, and therapeutic resistance. Hypoxia activates HIF1α, a key regulator that modulates the expression of genes involved in metabolic reprogramming and angiogenesis. Hypoxia disrupts protein homeostasis by compromising endoplasmic reticulum (ER) function, resulting in ER stress (ERS) and subsequent activation of the ER stress response (ERSR), collectively known as the unfolded protein response (UPR). Hypoxic stress also induces DNA damage and genomic instability, driven by replication stress and dysregulated DNA damage repair (DDR) pathways. In this review, we examine the current understanding of the mechanisms by which UPR sensors interface with DDR components to influence cancer cell fate under hypoxic conditions. Elucidating the mechanistic crosstalk among these hypoxia-responsive stress pathways will provide a better understanding of tumor evolution and metastasis. Furthermore, it highlights the cellular vulnerabilities emerging from this interplay that may be leveraged for therapeutic interventions.
    Keywords:  DNA damage response (DDR); ER stress (ERS); hypoxia; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1002/ijc.70443
  3. Cells. 2026 Mar 09. pii: 486. [Epub ahead of print]15(5):
    ER Proteotoxic Stress Drives Mitochondrial Dysfunction in Heat-Stressed Intestinal Epithelial Cells.
    Shuai Gao, Xiaocong Zheng, Yi Jiang, Feifan Zhang, Wengang Pei, Guang Yang, Guangliang Liu.
      Global climate change has increased the frequency and intensity of heat waves, posing a significant threat to livestock production. During heat exposure, the disruption of intestinal barrier integrity is a pivotal event in the pathogenesis of heat stress-induced intestinal injury. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are key consequences of heat stress at the cellular level. However, direct causal evidence linking ER stress to mitochondrial dysfunction in heat-stressed enterocytes remains limited. To investigate this, we used an integrated transcriptomic, metabolomic, and functional validation strategy to assess mitochondrial bioenergetics and cellular ultrastructure in porcine intestinal epithelial (IPEC-J2) cells under acute heat stress. Transcriptomic analysis revealed extensive reprogramming, highlighting the significant enrichment of pathways related to protein processing in the endoplasmic reticulum, apoptosis, and MAPK signaling. Untargeted metabolomics identified significant perturbations in amino acid and energy metabolism, as well as altered bile acid profiles. Functional assessments confirmed that heat stress severely impaired mitochondrial bioenergetics, as evidenced by reduced maximal respiration and ATP production, and induced ultrastructural damage to mitochondria. The pharmacological inhibition of ER stress by 4-phenylbutyric acid (4-PBA) significantly attenuated the mitochondrial bioenergetic impairment and ultrastructural damage, whereas ER stress induction recapitulated these defects. We demonstrate that heat stress induces profound transcriptional and metabolic remodeling characterized by ER stress activation, which critically mediates subsequent mitochondrial bioenergetic dysfunction and ultrastructural damage. Our findings suggest that targeting ER stress may represent a promising therapeutic strategy to ameliorate enterocyte mitochondrial dysfunction and mitigate heat stress-induced intestinal injury in livestock.
    Keywords:  endoplasmic reticulum stress; heat stress; intestinal epithelium; mitochondrial dysfunction; multi-omics
    DOI:  https://doi.org/10.3390/cells15050486
  4. FASEB J. 2026 Mar 31. 40(6): e71652
    Weight Loss During Obesity Provokes Asparaginase-Associated Liver Steatosis and Endoplasmic Reticulum Stress.
    Chintan T Bhavsar, Brian A Zalma, Keigo Tomoo, Yi Zhang, Esther M Lopez, Emily T Mirek, Joseph L Dixon, Gregory C Henderson, Ronald C Wek, Tracy G Anthony.
      Asparaginase is an anti-leukemic agent that triggers severe adverse metabolic events. Obesity is a known risk factor for asparaginase-associated liver steatosis. To better understand why, we first compared the liver metabolome of lean versus diet-induced obese (DIO) mice exposed to native asparaginase and observed a substantially altered liver metabolome in DIO mice only. To explore the basis for the altered liver metabolome in DIO mice, we designed experiments to clarify the relative contributions of obesity versus feeding excessive fat during asparaginase on liver triglycerides. Lean mice and DIO mice were fed a high-fat, obesogenic diet (OD) or low fat, maintenance diet (MD) during exposure to pegylated (PEG)-asparaginase. In lean mice, feeding OD during PEG-asparaginase modestly (2-fold) increased liver steatosis. Obese mice fed OD during PEG-asparaginase showed the lowest food intake alongside the lowest liver triglyceride secretion rates, resulting in the largest (6-fold) increase in liver triglycerides and emergent endoplasmic reticulum (ER) stress. Switching obese mice to a MD during PEG-asparaginase did not rescue liver steatosis nor alleviate ER stress. In a separate study, DIO mice globally lacking albumin (AlbKO) were fed OD during exposure to PEG-asparaginase to examine if loss of the major plasma free fatty acid carrier could lessen liver steatosis, but loss of circulating albumin did not mitigate elevated liver triglycerides. In total, the results revealed that body weight loss enables asparaginase-associated liver steatosis and ER stress. Mitigating asparaginase-induced weight loss may be a meaningful strategy in preventing liver stress during treatment.
    Keywords:  PERK; free fatty acids; gene expression; lipoproteins
    DOI:  https://doi.org/10.1096/fj.202503617RR
  5. Front Immunol. 2026 ;17 1737504
    D-allose suppresses colitis associated carcinogenesis by reversing ER stress in macrophages and inhibiting cancer cell proliferation.
    Xiaodong Li, Keizo Hiraishi, Kensuke Kumamoto, Shin-Ichi Nakakita, Tetsuo Yamashita, Kazuyo Kamitori, Kiyomi Ohmichi, Ryou Ishikawa, Lin Hai Kurahara.
       Introduction: Inflammatory bowel diseases (IBD), especially ulcerative colitis, are associated with a high risk of carcinogenesis. D-allose, a D-glucose epimer, exhibits antioxidant and antitumor activities. This study aimed to examine the effects of D-allose on colitis-associated carcinogenesis.
    Methods: A mouse model of colitis-associated carcinogenesis was established followed by treatment with D-allose. In vitro, ER stress and mitochondrial function in RAW 264.7 macrophages and the migration and proliferation of Caco-2 cells were analyzed to elucidate the underlying mechanisms. Colonic tissues obtained from IBD patients with were subjected to analyze ER stress in macrophages.
    Results: D-allose administration significantly reduced the tumor number, hemorrhage, inflammation score, and macrophage infiltration in the AOM/DSS model. D-allose suppressed ER stress signal and mitochondrial dysfunction in LPS treated RAW 264.7 macrophages. D-allose suppressed ER stress marker Bip and CHOP expression in thapsigargin treated RAW 264.7. In IBD patient's colon, ER stress marker Bip and CHOP positive macrophage infiltration was detected in both inflammatory and tumor areas. The level of fluorescence labeled M6~G1M9 oligosaccharides increased in the LPS-treated RAW 264.7 macrophages, while thapsigargin or D-allose had no effect. In Caco-2 cells, D-allose suppressed phosphorylated AMPK expression, reduced migratory activity. D-allose inhibited glycolysis, and decreased cell proliferation through TXNIP upregulation.
    Conclusion: D-allose suppressed inflammation and tumor development in a colitis-associated carcinogenesis model. D-allose restoring macrophage ER stress and mitochondrial dysfunction, and inhibiting colon cancer cell migration and proliferation. Therefore, D-allose may represent as a promising therapeutic and preventive agent for IBD and inflammation-associated carcinogenesis.
    Keywords:  D-allose; ER stress; carcinogenesis; colitis; macrophages; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fimmu.2026.1737504
  6. RSC Chem Biol. 2026 Feb 26.
    Chemical modulation of the unfolded protein response reveals an antiviral role for the PERK pathway in human coronavirus 229E infection.
    Isabella E Pellizzari-Delano, Trinity H Tooley, Debanjana Mondal, Keya Jani, Carla E Gallardo-Flores, Che C Colpitts.
      Broad spectrum antivirals are critical to respond rapidly to the threat posed by newly emerging RNA viruses. One potential candidate is the natural compound thapsigargin (Tg). Tg potently induces endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR). Recent studies have demonstrated that Tg has robust antiviral activity against several human coronaviruses (CoVs), including SARS-CoV-2, although the specific antiviral mechanism(s) have remained unclear. Here, we aimed to characterize the role of the UPR in the antiviral activity of Tg against HCoV-229E, a model common cold CoV. Consistent with previous findings, we show that a short 30-minute priming of A549 cells with Tg potently inhibits HCoV-229E infection. Time-of-addition assays showed that Tg is most effective when added up to 8 hours post-infection. Furthermore, Tg inhibits the accumulation of double-stranded RNA in infected cells, suggesting that Tg inhibits early stages of viral RNA replication. Using selective UPR pathway inhibitors to narrow down the role of these pathways in mediating the antiviral effect of Tg, we show that the inhibition of IRE1 or ATF6 does not impair the ability of Tg to inhibit HCoV-229E infection. The use of stable knockdown A549 cells in which IRE1, PERK, or ATF6 expression was silenced further revealed that the antiviral activity of Tg is not dependent on the expression of any of the three UPR sensors individually. However, HCoV-229E replication is inhibited in A549-shIRE1 cells, or in cells treated with the IRE1 inhibitor (KIRA6), suggesting that IRE1 activation may play a pro-viral role during HCoV-229E infection. Selective UPR pathway activators were used to further probe down the role of each pathway during HCoV-229E infection. Activation of the PERK pathway, but not IRE1 or ATF6 pathways, inhibits HCoV-229E infection. Lastly, to more broadly test the antiviral role of PERK against CoV RNA replication, we used BHK-21 cells that stably express a SARS-CoV-2 replicon. We show that PERK activation inhibits SARS-CoV-2 replication similarly to Tg. Overall, these findings provide insight into the antiviral mechanism(s) of Tg against CoV infection and demonstrate that modulation of the UPR may be exploited as an antiviral strategy.
    DOI:  https://doi.org/10.1039/d5cb00242g
  7. J Lipid Res. 2026 Mar 09. pii: S0022-2275(26)00043-X. [Epub ahead of print] 101017
    S-nitrosylation contributes to ER stress and aggresome formation in Secosterol-B-mediated endothelial dysfunction.
    Maria Gemma Nasoni, Erik Bargagni, Francesca Monittola, Pasquale Creanza, Elisa Maricchiolo, Sofia Masini, Anastasia Ricci, Serena Benedetti, Silvia Carloni, Sabrina Burattini, Alessandra Fraternale, Andrea Pompa, Michele Menotta, Luigi Iuliano, Rita Crinelli, Francesca Luchetti.
      The involvement and the in vivo relevance of endoplasmic reticulum (ER) stress in the atherosclerotic process are well established, but the mechanisms have been only partly elucidated. Emerging evidence indicates that ER protein folding pathways are sensitive to nitric oxide (NO) fluctuations and therefore heavily vulnerable under conditions of nitrosative stress (NSS). Recent research indicates that protein S-nitrosylation (-SNO), a key redox-mediated modification involved in several disorders, affects neuronal function by altering ER stress sensor proteins. However, the mechanisms by which ER proteins S-nitrosylation impact vascular diseases remain unclear. Here, we provide evidence that secosterol-B, an oxysterol found in atherosclerotic plaques, induces NSS and protein S-nitrosylation in vascular endothelium leading to ER stress. In detail, our findings demonstrate that secosterol-B triggers activation of the IRE/XBP-1 signaling pathway and causes ER-membrane expansion and the accumulation of misfolded proteins in human umbilical vein endothelial cells (HUVECs). In parallel, increased NO levels with up-regulation of iNOS protein expression and alterations in the nitrosylation levels of various proteins, including PDI and GRP78, were observed. Interestingly, pretreatment with L-NAME strongly reduced ER swelling and aggresome formation. Collectively, our findings demonstrate that NO and protein S-nitrosylation play a critical role in secosterol-B-induced ER dysfunction, providing new insights into the mechanisms underlying vascular dysfunction observed in atherosclerosis and highlighting potential therapeutic targets to preserve endothelial integrity.
    Keywords:  GRP78; HUVECs; UPR; atherosclerosis; misfolded proteins; nitric oxide; nitrosative stress; oxysterols; proteomics
    DOI:  https://doi.org/10.1016/j.jlr.2026.101017
  8. Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2514355123
    Ubiquitin-specific peptidase-19 links TDP-43 aggregation to ER stress.
    Yan Yan, Xinming Wang, Hanna Jeon, Teresa R Kee, Khoi D Tran, Hyunkyoung Lee, Xingyu Zhao, Tian Liu, Simon S Wing, Jung-A A Woo, David E Kang.
      Aggregation and deposition of TAR DNA-binding protein 43 (TDP-43) is a salient pathological signature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration-TDP (FTLD-TDP). TDP-43 proteostasis and aggregation are controlled by several posttranslational modifications, including ubiquitination. While multiple E3 ubiquitin ligases are known to facilitate TDP-43 clearance, little is known about the role of deubiquitinases (DUBs) in controlling TDP-43 proteostasis. Through an unbiased discovery screen of DUBs, here we identify and demonstrate using in vitro and in vivo models, as well as human brain tissue, that ubiquitin-specific peptidase-19 (USP19) acts as a TDP-43-directed DUB that removes K48- and K63-linked ubiquitin conjugates from TDP-43 and preferentially promotes cytoplasmic aggregation of TDP-43 C-terminal fragments (TDP-CTFs) through its catalytic activity. Specifically, the endoplasmic reticulum (ER)-anchored USP19 isoform (USP19-ER) exhibits superior activity in deubiquitinating TDP-CTFs, enhancing its phase separation and aggregation, compared to its cytosolic isoform (USP19-Cyto). Furthermore, as TDP-CTFs are generated at the ER, USP19 acts to couple the aggregation of TDP-CTFs to ER stress (ATF6, ATF4, IRE1, & CHOP). In humans, USP19 protein levels increase in FTLD-TDP brains, which extensively colocalize with cytoplasmic phospho-TDP-43 (pTDP-43) pathology. Importantly, we demonstrate in vivo that genetic reduction of usp19 mitigates pTDP-43 pathology, astrogliosis, and ER stress while reversing long-term potentiation (LTP) and motor deficits in a mouse model of TDP-43 pathogenesis (TAR4 mice). These findings establish a critical role of USP19 at the nexus of TDP-43 proteostasis and ER stress, implicating its pathogenic role in FTLD-TDP and ALS.
    Keywords:  ALS; ER stress; FTD; TDP-43; USP19
    DOI:  https://doi.org/10.1073/pnas.2514355123
  9. Cell Death Dis. 2026 Mar 09.
    Small molecule screening identifies cytotoxic endoplasmic reticulum-associated degradation inhibitors in multiple myeloma.
    Erin M Kropp, Sho Matono, Olivia Y Wang, Aaron M Robida, Malathi Kandarpa, Jineigh L Grant, Bryndon J Oleson, Andrew Alt, Moshe Talpaz, Matthew J Pianko, Qing Li.
      Multiple myeloma (MM) is an incurable plasma cell neoplasm that is highly reliant on endoplasmic reticulum-associated degradation (ERAD) to maintain protein homeostasis. Disrupting ERAD has been proposed as a therapeutic strategy to overcome proteasome inhibitor resistance; however, the identification of novel inhibitors has been limited. To address this, we conducted a cell-based high-throughput screen using the FDA repurposing library and identified omaveloxolone (RTA408) as a potent ERAD inhibitor that selectively impairs the degradation of ER luminal and membrane substrates, without affecting the degradation of key cytosolic proteins that are implicated in disease relapse. Surprisingly, although ER stress response pathways are activated after ERAD inhibition in MM, we find that apoptosis is mediated by altered lipid raft organization, leading to aberrant activation of the death-inducing signaling complex (DISC) and caspase 8 in the extrinsic apoptotic pathway. Notably, ERAD inhibition by RTA408 is cytotoxic to primary malignant plasma cells, including those resistant to proteasome inhibitors, and demonstrates in vivo anti-myeloma activity. Our findings establish a novel ERAD inhibitor, which is a valuable tool to dissect ERAD biology, and provide pre-clinical evidence for RTA408 as a therapeutic agent in MM.
    DOI:  https://doi.org/10.1038/s41419-026-08526-2
  10. Int J Mol Sci. 2026 Feb 27. pii: 2234. [Epub ahead of print]27(5):
    Crosstalk Between Autophagy and Paraptosis: A New Frontier in Cancer Therapy.
    Sweata Hanson, Deiviga Murugan, Palli V Jinsha, Anupama Binoy, Bipin G Nair, Nandita Mishra.
      Autophagy and paraptosis are two distinct physiological mechanisms involved in regulating cell fate in cancer. Recent studies have demonstrated that autophagy is a crucial process for maintaining cellular homeostasis by facilitating the removal of misfolded proteins and damaged organelles. However, autophagy is found to play a dual role in cancer. Severe ER and mitochondrial dysfunction can trigger different forms of programmed cell death, including autophagic cell death. In cancer cells that evade apoptosis, paraptosis, a caspase-independent alternate death pathway, is triggered by ER and mitochondrial swelling, leading to extensive cytoplasmic vacuolation. It can be induced by natural compounds, metallic complexes, nanoparticles, or chemotherapeutic agents, primarily through excessive ROS production and disruption of protein, thiol, and calcium/ion homeostasis. Autophagy and paraptosis have been found to be connected through crosstalk. While MAPK activation drives paraptosis, ER stress and the unfolded protein response (UPR) can initiate both paraptosis and autophagy. UPR-mediated PERK activation promotes survival autophagy in ER-stressed melanoma, whereas PERK elimination triggers paraptosis via sec61β with unresolved ER stress. Similarly, CHOP and DDIT4 can enhance ER stress and proteotoxicity, thereby favouring paraptosis. This review is unique in exploring the dynamic interplay between autophagy and paraptosis in cancer cells, highlighting promising therapeutic targets for chemotherapy-resistant cancers.
    Keywords:  ER stress; autophagy; cancer; crosstalk; mitochondrial dysfunction; paraptosis
    DOI:  https://doi.org/10.3390/ijms27052234
  11. Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2510886123
    Hypothalamic endoplasmic reticulum stress drives pubertal precocity due to early-onset obesity in female rodents.
    Elvira Rodríguez-Vázquez, Álvaro Aranda-Torrecillas, Manuel Jiménez-Puyer, Oscar Freire-Agulleiro, María J Sánchez-Tapia, Miguel Ruiz-Cruz, Violeta Heras, María López-Sancho, Luisina Ongaro, Cecilia Perdices-López, Daniel J Bernard, Rafael Pineda, Francisco Gaytan, Miguel López, Juan M Castellano, Manuel Tena-Sempere.
      Early-onset obesity, especially in girls, is frequently associated with advanced puberty; a phenomenon bound to increased risk of long-term complications. Hypothalamic endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of obesity and its comorbidities. However, its contribution to pubertal disorders associated with obesity remains unexplored. We report herein that central ER stress drives obesity-induced precocious female puberty. Hypothalamic expression of key ER stress markers was blunted during normal pubertal transition and altered in female rats with early-onset obesity and advanced puberty, which displayed increased levels of p-PERK and p-eIF2α, and reduced ATF6α content. Central stimulation of hypothalamic ER stress with Thapsigargin in prepuberal lean female rats mimicked advanced puberty onset caused by obesity, without changes in body weight. This phenomenon seemingly involves a circuit including the hypothalamic arcuate nucleus (ARC), since obesity-induced precocious puberty was largely prevented by alleviation of ER stress via virogenetic overexpression of the ER chaperone, GRP78, in the ARC, but not in the paraventricular nucleus, in female rats. In addition, expression analyses of ER stress markers in mouse Kiss1 neurons isolated from juvenile and pubertal female mice revealed increased expression of Perk and Ire1α mRNAs in Kiss1ARC neurons in early-overfed mice at the juvenile stage, while Xbp1s/u expression ratio was significantly increased during juvenile-pubertal transition in overweighed mice. Collectively, our data uncover a relevant role of hypothalamic ER stress in the control of female puberty and the pathogenesis of obesity-induced pubertal alterations.
    Keywords:  ER stress; Kiss1 neurons; hypothalamus; obesity; puberty
    DOI:  https://doi.org/10.1073/pnas.2510886123
  12. Cell Rep. 2026 Mar 12. pii: S2211-1247(26)00161-0. [Epub ahead of print]45(3): 117083
    IRE1α regulates macrophage phagocytosis in immune thrombocytopenia through NR1D1 mRNA decay and lysosomal biogenesis.
    Yushan Xu, Fangling Zhao, Mengjiao Lin, Zhewen Qin, Yi Zheng, Ni Yao, Xingxing Chen, Bei Zhang, Dawei Cui, Ziyin Yang, Bo Shan, Jue Xie.
      Macrophage phagocytosis is essential for immune homeostasis but must be tightly constrained to prevent pathological tissue damage. How cellular stress pathways enforce phagocytic homeostasis remains incompletely understood. Here, we show that phagocytosis selectively activates the endoplasmic reticulum stress sensor IRE1α in macrophages, which functions as a negative regulator of lysosome-driven phagocytic amplification. Using myeloid-specific IRE1α-deficient mice and pharmacological inhibition, we demonstrate that loss of IRE1α RNase activity leads to excessive phagocytosis through unchecked lysosomal biogenesis. Mechanistically, phagocytosis-activated IRE1α directly degrades Nr1d1 mRNA via regulated IRE1α-dependent decay (RIDD), thereby restraining NR1D1-driven lysosomal expansion. Disruption of this IRE1α-NR1D1 axis exacerbates macrophage-mediated platelet clearance and accelerates disease progression of immune thrombocytopenia (ITP). Reduced ERN1 expression and IRE1α activity are observed in monocytes from patients with ITP. Pharmacological inhibition of NR1D1 or lysosomal activity rescues thrombocytopenia. Together, these findings establish the IRE1α-NR1D1-lysosome axis as a therapeutically actionable pathway in phagocytosis-driven diseases.
    Keywords:  CP: immunology; IRE1α; IRE1α-dependent decay; Nr1d1; SR8278; endoplasmic reticulum stress; immune thrombocytopenia; lysosomal biogenesis; macrophage phagocytosis; unfolded protein response
    DOI:  https://doi.org/10.1016/j.celrep.2026.117083
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