bims-unfpre 2025-06-22 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–06–22
eight papers selected by
Susan Logue, University of Manitoba

Targeting endoplasmic reticulum proteostasis in liver fibrosis: From signaling mechanisms to therapeutic opportunities.
Endoplasmic reticulum stress pathways and cellular death mechanisms in patients with phenylketonuria.
Therapeutic potential of BOLD-100, a GRP78 inhibitor, enhanced by ATR inhibition in pancreatic ductal adenocarcinoma.
Transgenic expression of endoplasmic reticulum proteins in C. elegans neurons is prone to causing ER stress.
Neocarzilin A induces apoptosis and mitochondrial disturbance by targeting reticulon 4-mediated endoplasmic reticulum stress.
Unfolded protein response in endoplasmic reticulum stress associated with retinal degenerative diseases: A promising therapeutic target.
SREBF1 mediates immunoparalysis of dendritic cells in sepsis by regulating lipid metabolism and endoplasmic reticulum stress.
Metformin modulates the unfolded protein responses, altering lifespan and health-promoting effects in UPR-activated worms.

Pharmacol Res. 2025 Jun 11. pii: S1043-6618(25)00248-8. [Epub ahead of print]217 107823

Targeting endoplasmic reticulum proteostasis in liver fibrosis: From signaling mechanisms to therapeutic opportunities.

Yawei Kong, Zhengyang Chen, Zhentian Nie, Wei Chen.

  Liver fibrosis, a progressive consequence of chronic liver disease, is characterized by excessive extracellular matrix (ECM) deposition and persistent inflammation. It poses a substantial global health burden, particularly among individuals with obesity, excessive alcohol intake, or chronic viral hepatitis. Increasing evidence suggests that endoplasmic reticulum (ER) stress plays a critical role in fibrogenesis by disrupting cellular homeostasis and activating pathological signaling pathways. This review offers a comprehensive overview of the mechanisms driving liver fibrosis, with a particular emphasis on ER stress-associated pathways, including ER-associated degradation (ERAD), the unfolded protein response (UPR), and autophagy. We further discuss the impact of chronic ER stress on hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells (KCs), emphasizing their roles in fibrosis progression. Finally, we explore therapeutic strategies targeting ER stress as potential antifibrotic interventions, providing novel insights into the treatment of liver fibrosis.

Keywords:  Endoplasmic reticulum stress; Liver fibrosis; Therapeutics; UPR

DOI:  https://doi.org/10.1016/j.phrs.2025.107823
Mol Biol Rep. 2025 Jun 16. 52(1): 597

Endoplasmic reticulum stress pathways and cellular death mechanisms in patients with phenylketonuria.

Hacer Esra Gürses Cila, Ali Dursun, Neşe Vardar Acar, Neslihan Nisa Geçici, Selda Ayhan, Sevil Oskay Halaçlı, R Köksal Özgül.

   BACKGROUND: Phenylketonuria (PKU) is an inherited metabolic disease of amino acid metabolism characterized by the deficiency of activity in phenylalanine (Phe) hydroxylase enzyme, leading to the accumulation of Phe and its metabolites in the blood and tissues of affected patients. PKU, caused by various mutations leading to misfolded or nonfunctional proteins in the cells, still has an incompletely understood pathophysiology. This study aims to investigate the role of endoplasmic reticulum (ER) stress and ER stress response in PKU pathophysiology.
METHODS AND RESULTS: Peripheral blood mononuclear cells (PBMCs) isolated from PKU patients carrying distinct protein misfolding mutations were analyzed to investigate the involvement of ER stress-related gene expression and cell death pathways. A comprehensive evaluation was conducted using quantitative real-time PCR and flow cytometry under both physiological (basal) conditions and following Phe administration, with the aim of elucidating the molecular mechanisms underlying Phe-induced cellular stress. Our results demonstrates that PKU patients exhibit a response to ER stress mediated by the IRE1 and ATF6 pathways of the UPR. We also observe disruptions in autophagic flux, as shown by the expression results of LC3B and p62 proteins. Importantly, the PBMCs do not appear to undergo immediate apoptotic cell death. The avoidance of apoptosis induction, even in the context of acute Phe treatment in the PBMCs of PKU patients who have been chronically exposed to ER stress, indicates an adaptive mechanism that facilitates cellular survival in these patients.
CONCLUSIONS: By focusing on the ER stress response in PKU patients with different type of mutations leading to protein misfolding, this study has the potential to provide new insights into PKU pathophysiology.

Keywords:  Apoptosis; Autophagy; ER stress; Phenylketonuria; Protein folding defect; UPR pathway

DOI:  https://doi.org/10.1007/s11033-025-10681-2
Cell Commun Signal. 2025 Jun 13. 23(1): 281

Therapeutic potential of BOLD-100, a GRP78 inhibitor, enhanced by ATR inhibition in pancreatic ductal adenocarcinoma.

Su In Lee, Ah-Rong Nam, Kyoung-Seok Oh, Jae-Min Kim, Ju-Hee Bang, Yoojin Jeong, Sea Young Choo, Hyo Jung Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh.

  Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and resistance to conventional therapies, necessitating novel treatments. The high proliferative rate and protein synthesis in PDAC induce endoplasmic reticulum (ER) stress, with Glucose-Regulated Protein 78 (GRP78), a key regulator of ER stress and the Unfolded Protein Response (UPR), playing a pivotal role in PDAC progression. Despite its relevance, GRP78-targeted therapies remain unexplored in PDAC. BOLD-100, a novel GRP78 inhibitor, presents a potential therapeutic approach by disrupting GRP78 transcription, though its effects on PDAC have yet to be fully elucidated. Here, we found that BOLD-100 induces PDAC cell death through the UPR pathway activation, leading to CHOP-dependent apoptosis. BOLD-100 generates reactive oxygen species (ROS), inducing R-loop formation that triggers a DNA damage response via the ATR/Chk1 axis. BOLD-100 synergizes with AZD6738, an ATR inhibitor, to enhance anti-tumor efficacy compared to either agent alone in both in vitro and in vivo models. These findings suggest that BOLD-100, especially in combination with an ATR inhibitor, represents a promising therapeutic option for patients with PDAC.

Keywords:  ATR; CHOP; DNA damage response; ER stress; GRP78; Pancreatic cancer; ROS

DOI:  https://doi.org/10.1186/s12964-025-02242-8
MicroPubl Biol. 2025 ;2025

Transgenic expression of endoplasmic reticulum proteins in C. elegans neurons is prone to causing ER stress.

Junhyun Park, Shaul Yogev.

In studying the endomembrane system, organelle-specific markers tagged with fluorescent proteins are used to visualize individual organelles. However, whether the expression of organelle marker perturbs the organelle's biology is not always apparent. We report that expression of a GFP-tagged Endoplasmic Reticulum (ER) protein causes low levels of ER stress that are challenging to detect in control animals. This stress is revealed only once the ER-associated degradation (ERAD) pathway is compromised. Our results highlight the vulnerability of the ER and suggest that the possible contribution of ER stress to phenotypes obtained with transgenic markers should be considered when interpreting the phenotypes.

DOI: https://doi.org/10.17912/micropub.biology.001547
Cell Death Discov. 2025 Jun 16. 11(1): 278

Neocarzilin A induces apoptosis and mitochondrial disturbance by targeting reticulon 4-mediated endoplasmic reticulum stress.

A T Jauch, J Sailer, J Braun, E Czeslik, J Geyer, C Eberhagen, A M Vollmar, H Zischka, S A Sieber, S Zahler.

Natural compounds are a valuable source of highly active biomolecules for the discovery of innovative drug targets as well as drug leads. The natural compound neocarzilin A (NCA) exhibits pronounced antiproliferative and antimigratory activity, which we previously ascribed to the target proteins vesicle amine transporter protein 1 (VAT-1) and bone marrow stromal antigen 2 (BST-2). We here additionally demonstrate the perturbation of mitochondrial functions (fragmentation of mitochondrial networks, ultrastructural changes, increased Opa1 splicing, loss of mitochondrial membrane potential, and excessive ROS generation) upon treatment with NCA. We observe impairment of the electron transfer chain and diminished ATP synthesis. Furthermore, NCA triggers apoptosis via activation of caspase-8, enhanced Bid processing, and cytochrome c release from mitochondria into the cytosol, leading to the activation of caspase-3 and -9 and, finally, PARP cleavage and DNA fragmentation. Endoplasmic reticulum (ER) stress is induced by treatment with NCA, and subsequently, the unfolded protein response (UPR) via the protein kinase r-like ER kinase (PERK) branch is prompted. Proteomic ABPP data indicate reticulon 4 (Rtn4, Nogo), an ER-located protein mainly involved in shaping ER tubules and maintaining proper ER function, as a promising hit to explain those effects. This novel molecular target was verified by co-staining of the target probe NC-4 and Rtn4, as well as RNA interference experiments, which resulted in reduced responsiveness of HeLa cells to NCA treatment. We propose NCA as a powerful tool to study the biology of Rtn4, and to develop more specific modulators of reticulons in the future. Furthermore, we introduce-to our knowledge-the first small molecular modulator of reticulon proteins.

DOI: https://doi.org/10.1038/s41420-025-02560-3
Neural Regen Res. 2025 Jun 19.

Unfolded protein response in endoplasmic reticulum stress associated with retinal degenerative diseases: A promising therapeutic target.

Hongbing Zhang, Yalin Mu, Hongsong Li, Xiaogang Li.

   ABSTRACT: The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins. However, if the unfolded protein response fails to restore endoplasmic reticulum homeostasis, it can trigger proinflammatory and pro-death signals, which are implicated in various malignancies and are currently being investigated for their role in retinal degenerative diseases. This paper reviews the role of the unfolded protein responsein addressing endoplasmic reticulumstress in retinal degenerative diseases. The accumulation of ubiquitylated misfolded proteins can lead to rapid destabilization of the proteome and cellular demise. Targeting endoplasmic reticulum stress to alleviate retinal pathologies involves multiple strategies, including the use of chemical chaperones such as 4-phenylbutyric acid and tauroursodeoxycholic acid, which enhance protein folding and reduce endoplasmic reticulum stress. Small molecule modulators that influence endoplasmic reticulum stress sensors, including those that increase the expression of the endoplasmic reticulum stress regulator X-box binding protein 1, are also potential therapeutic agents. Additionally, inhibitors of the RNAse activity of inositol-requiring transmembrane kinase/endoribonuclease 1, a key endoplasmic reticulum stress sensor, represent another class of drugs that could prevent the formation of toxic aggregates. The activation of nuclear receptors, such as PPAR and FXR, may also help mitigate ER stress. Furthermore, enhancing proteolysis through the induction of autophagy or the inhibition of deubiquitinating enzymes can assist in clearing misfolded proteins. Combination treatments that involve endoplasmicreticulum-stress-targeting drugs and gene therapies are also being explored. Despite these potential therapeutic strategies, significant challenges remain in targeting endoplasmic reticulum stress for the treatment of retinal degeneration, and further research is essential to elucidate the mechanisms underlying human retinal diseases and to develop effective, well-tolerated drugs. The use of existing drugs that target inositol-requiring transmembrane kinase/endoribonuclease 1 and X-box binding protein 1 has been associated with adverse side effects, which have hindered their clinical translation. Moreover, signaling pathways downstream of endoplasmic reticulum stress sensors can contribute to therapy resistance. Addressing these limitations is crucial for developing drugs that can be effectively used in treating retinal dystrophies. In conclusion, while the unfolded protein response is a promising therapeutic target in retinal degenerative diseases, additional research and development efforts are imperative to overcome the current limitations and improve patient outcomes.

Keywords:  age-related macular degeneration; autophagy; diabetic retinopathy; endoplasmic reticulum stress; inflammasome; inflammation; mitochondrial diseases; mutation; nuclear receptors; photoreceptor cells; proteostasis; proteotoxic stress; retinal diseases; retinitis pigmentosa

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01124
Cell Commun Signal. 2025 Jun 16. 23(1): 286

SREBF1 mediates immunoparalysis of dendritic cells in sepsis by regulating lipid metabolism and endoplasmic reticulum stress.

Yaolu Zhang, Fangfang Wu, Yan Li, Jiaxin Liu, Liuyan Zhu, Min Zhang, Zhongqiu Lu.

   BACKGROUND: Lipid metabolic reprogramming is a key feature of sepsis, with increased lipid storage contributing to disease progression. Although lipid metabolism dysregulation has been implicated in sepsis pathogenesis, how lipid biosynthesis, particularly mediated by sterol regulatory element-binding transcription factor 1 (SREBF1), leads to dendritic cell (DC) immunoparalysis remains unclear.
METHODS: Intracellular lipid accumulation was assessed by Oil Red O and BODIPY staining. Gene and protein expression levels were analyzed via qPCR, Western blot, and immunofluorescence. SREBF1 activity was modulated using genetic knockout and siRNA silencing. DC phenotype and CD4+ T cell proliferation were evaluated using flow cytometry and co-culture assays. Cytokine secretion was measured using ELISA.
RESULTS: In a cecal ligation and puncture-induced sepsis model, we observed increased lipid biosynthesis and significantly elevated SREBF1 expression in spleen DCs. Increased SREBF1 expression suppressed the expression of costimulatory molecules (e.g., CD40, CD80, and CD86) and MHC II, reduced the secretion of inflammatory cytokines (e.g., TNFα, IL-1β, IL-6, and IL-12), impaired CD4+ T cell activation, and promoted apoptosis. Mechanistically, SREBF1 activation enhanced lipid biosynthesis in DCs, which triggered endoplasmic reticulum (ER) stress, as evidenced by increased PERK phosphorylation, eIF2α activation, and subsequent ATF4/CHOP induction. SREBF1 silencing attenuated the lipid-induced ER stress and restored DC function, whereas tunicamycin treatment partially reversed these protective effects.
CONCLUSIONS: Our study identifies SREBF1 as a central regulator of sepsis-induced DC immunoparalysis by coupling lipid metabolic reprogramming to ER stress activation. Targeting this SREBF1-lipid-ER stress axis represents a novel strategy to reverse immunosuppression in septic patients.

Keywords:  Dendritic cells; Endoplasmic reticulum stress; Lipid metabolism; SREBF1; Sepsis

DOI:  https://doi.org/10.1186/s12964-025-02295-9
PLoS One. 2025 ;20(6): e0326100

Metformin modulates the unfolded protein responses, altering lifespan and health-promoting effects in UPR-activated worms.

Jerald Tan, Chutipong Chiamkunakorn, Kanpapat Boonchuay, Yiying Shi, Bart P Braeckman, Wichit Suthammarak.

Metformin has been demonstrated to extend lifespan in various model organisms, and its molecular effects are observed in the cytoplasm and multiple organelles, including mitochondria. However, its association with the unfolded protein response (UPR) and its impact on stress resistance and locomotion remain uncertain. In this study, metformin was found to exert differential influences on both UPRmt and UPRer. The correlation between metformin's lifespan-mediating effect and its interaction with UPRs was also inconsistent. We identified a metformin-mediated lifespan extension in wild-type C. elegans and in UPRmt-activated tomm-22 and cco-1 RNAi worms. Metformin suppressed the UPRmt without compromising the lifespan extension observed in tomm-22 worms. Conversely, metformin did not affect the UPRmt but extended the lifespan of long-lived cco-1 RNAi worms. Furthermore, we investigated the effects of metformin on UPRer-activated nematodes. We observed that metformin exhibited a slight increase in the UPRer in mdt-15 RNAi worms and failed to induce lifespan extension. Surprisingly, metformin appeared to mediate lifespan extension in tmem-131 RNAi worms while suppressing the UPRer. Notably, the correlation between thermotolerance, oxidative stress resistance, and the lifespan effects of metformin in UPR-activated worms was inconsistent. Activation of UPRs, but not metformin treatment, enhanced the locomotor phenotype of these worms.

DOI: https://doi.org/10.1371/journal.pone.0326100