bims-unfpre 2025-07-13 papers

Issue of 2025–07–13
five papers selected by
Susan Logue, University of Manitoba

Front Pharmacol. 2025 ;16 1595845

Research progress on endoplasmic reticulum homeostasis in acute kidney injury.

The endoplasmic reticulum (ER) is the most metabolically active organelle in cells, and recent research has shown that abnormal ER function is involved in the occurrence and development of acute kidney injury (AKI), but the underlying molecular mechanism needs to be further elucidated. Here, we review the biological functions of the ER in cellular metabolism, explore the current research progress on the role of the ER in different triggers of AKI, and summarize the ER stress inhibitors discovered thus far. Finally, we explore the possibility of targeting ER homeostasis as a therapeutic target for AKI.

Keywords: AKI; ER stress; UPR; endoplasmic reticulum (ER); kidney

DOI: https://doi.org/10.3389/fphar.2025.1595845

FASEB Bioadv. 2025 Jul;7(7): e70031

Endoplasmic Reticulum Stress and Unfolded Protein Response Sensor ERN1 Regulates Organic Dust Induction of Lung Inflammation.

Shilpa Kusampudi, Velmurugan Meganathan, Vijay Boggaram.

Inhalation of organic dust increases the risk for respiratory symptoms and respiratory diseases, with chronic inflammation playing a major role in their development. Previously, we reported that organic dust induction of inflammatory mediators in bronchial epithelial cells is mediated through increase of intracellular reactive oxygen species (ROS) and activation of NFκB and Stat3. Oxidative stress caused by increased ROS has been linked to the activation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR). UPR modulates immune responses and plays key roles in the development of acute and chronic diseases. Herein, we hypothesized that organic dust-induced ER stress-UPR regulates airway epithelial cell inflammatory responses. We found that poultry organic dust extract (referred to as dust extract) increased the expression of ER stress/UPR sensor ERN1 in Beas2B bronchial epithelial cells. Dust extract was also found to increase ERN1 protein levels in mouse lungs with ERN1 immunostaining detected predominantly in the bronchial epithelium. Additionally, dust extract increased Ser724 ERN1 phosphorylation in the mouse bronchial epithelium indicating activation. Chemical inhibition and mRNA knockdown studies revealed that TLR2/TLR4-Myd88-ROS-NFκB/Stat3 pathway mediates ERN1 induction. ERN1 chemical inhibitors, KIRA6 and APY29, and ERN1 mRNA knockdown reduced the induction of IL6, CXCL8, and pro IL1β. KIRA6 inhibited dust extract stimulation of NFκB-p65, Stat3, Jun and MAPK 8/9 phosphorylation. Our studies have shown that ER stress and ERN1 are new players in the control of organic dust induced lung inflammation. Cross-regulation between members of cell signaling cascade, TLR2-TLR4/MyD88/ROS/ERN1/NFκB/Stat3 may fine tune immune and inflammatory responses elicited by organic dust.

Keywords: endoplasmic reticulum stress; inflammation; lung; oxidative stress; unfolded protein response

DOI: https://doi.org/10.1096/fba.2025-00069

Nat Commun. 2025 Jul 07. 16(1): 6247

EMP1 safeguards hematopoietic stem cells by suppressing sphingolipid metabolism and alleviating endoplasmic reticulum stress.

Lei Li, Yufei Lei, Yan Li, Yuxin Xie, Pusheng Hui, Xiaoyan Zang, Weiru Wu, Feng Wu, Jiankun Fan, Jianming Wang, Jieping Chen, Zhe Chen, Yu Hou.

The long-term maintenance of hematopoietic stem cells (HSCs) relies on the regulation of endoplasmic reticulum (ER) stress at a low level, but the underlying mechanism remains poorly understood. Here, we demonstrate that suppression of ER stress improves the functions of HSCs and protects HSCs against ionizing radiation (IR)-induced injury. We identify epithelial membrane protein 1 (EMP1) as a key regulator that mitigates ER stress in HSCs. Emp1 deficiency leads to the accumulation of protein aggregates and elevated ER stress, ultimately resulting in impaired HSC maintenance and self-renewal. Mechanistically, EMP1 is located within the ER and interacts with ceramide synthase 2 (CERS2) to limit the production of a class of sphingolipids, dihydroceramides (dhCers). DhCers accumulate in Emp1-deficient HSCs and induce protein aggregation. Furthermore, Emp1 deficiency renders HSCs more susceptible to IR, while overexpression of Emp1 or inhibition of CERS2 protects HSCs against IR-induced injury. These findings highlight the critical role played by the EMP1-CERS2-dhCers axis in constraining ER stress and preserving HSC potential.

DOI: https://doi.org/10.1038/s41467-025-61552-0

Cancer Lett. 2025 Jul 03. pii: S0304-3835(25)00456-2. [Epub ahead of print] 217888

Endoplasmic Reticulum Stress-Driven Nucleotide Catabolism Fuels Prostate Cancer.

Ke Deng, Nora Pällmann, Marte Livgård, Wanja Kildal, Manohar Pradhan, Ladan Fazli, Paul S Rennie, Yang Jin, Fahri Saatcioglu, Omer Kuzu.

Endoplasmic reticulum (ER) stress is a critical regulator of cancer cell metabolism and survival. In this study, we elucidate the coordinated roles of two key ER stress mediators, Activating Transcription Factor 4 (ATF4) and X-box Binding Protein 1 spliced (XBP1s), in regulating purine homeostasis in prostate cancer (PCa) cells. We demonstrate that ATF4 directly upregulates Molybdenum Cofactor Sulfurase (MOCOS), a key enzyme in purine catabolism, while XBP1s induces the expression of xanthine dehydrogenase (XDH), the principal MOCOS target in this pathway. Knockdown of MOCOS significantly impairs PCa cell proliferation as well as prostatosphere and colony formation in vitro and inhibits tumor growth in preclinical mouse models of PCa. Mechanistically, MOCOS suppression leads to purine accumulation, disrupts pyrimidine synthesis, and causes nucleotide imbalance, resulting in replication fork stalling. This imbalance is also accompanied by a compromised glutathione-mediated antioxidant response, rendering the cells more susceptible to DNA damage. Importantly, targeting XDH, either genetically or biochemically, also significantly hinders PCa cell growth. Collectively, our data highlight the pivotal role of ER stress-mediated purine homeostasis in sustaining PCa cell growth.

DOI: https://doi.org/10.1016/j.canlet.2025.217888

bioRxiv. 2025 Jul 04. pii: 2025.06.30.662315. [Epub ahead of print]

Progressive Supranuclear Palsy PERK haplotype B selectively translates DLX1 promoting tau toxicity.

The unfolded protein response sensor PERK exists in haplotypes A and B. PERK-B confers increased risk for tauopathies like progressive supranuclear palsy (PSP), but the mechanisms distinguishing its function from PERK-A and contributing to its association with tauopathy remain unknown. Here, we developed a controlled cellular model for a pair-wise comparison of the two PERK haplotypes, finding their UPR functions nearly indistinguishable. However, a careful examination employing puromycin-based proteomics revealed that a subset of mRNA translation events were permissible under PERK-B, but not PERK-A, dependent UPR. One of the targets that escaped PERK-B suppression was the transcription factor DLX1, which is genetically linked to PSP risk. We found that DLX1 solubility shifted in human PSP brain tissue. Furthermore, silencing the fly homolog of DLX1 was sufficient to decrease tau-induced toxicity, in vivo. Our results detail the haplotype-specific PERK-B/DLX-1 pathway as a novel driver of tau pathology in cells, flies, and likely human brain, revealing new insights into PSP pathogenesis and potential therapeutic targets.

DOI: https://doi.org/10.1101/2025.06.30.662315