To investigate the roles of Krüppel-like factor 10 (KLF10) and its inhibitor KLF10-IN-1 in regulating high-glucose/hypoxia-induced RPE cell apoptosis and their involvement in diabetic retinopathy (DR). A DR mouse model was established using a high-fat, high-glucose diet and streptozotocin. An RPE cell model of high-glucose/hypoxia injury was constructed by culturing cells under high-glucose (30 mM) conditions in the presence of cobalt chloride (200µM). KLF10 expression, apoptosis, and endoplasmic reticulum (ER) stress levels were assessed. KLF10 expression was modulated with small interfering RNA and overexpression plasmids. Dual luciferase reporter assays were used to evaluated the regulatory effect of KLF10 on PERK. The PERK pathway was activated by CCT020312 and inhibited by GSK2606414 for rescue experiments. The protective effects of KLF10-IN-1 were validated in vitro and in vivo. KLF10 was highly expressed in RPE cells in DR model mice. After 48 hours of high-glucose/hypoxia exposure, hypoxia, inflammation, ER stress, and apoptosis were significantly exacerbated, accompanied by KLF10 upregulation. KLF10 knockdown suppressed apoptosis and ER stress, whereas KLF10 overexpression had the opposite effect. Western blotting confirmed KLF10 regulated PERK phosphorylation, and dual luciferase assays revealed that KLF10 transcriptionally activates PERK. KLF10 mediated apoptosis through the PERK/eIF2α/ATF4/CHOP pathway. Inhibiting this pathway with KLF10-IN-1 reduced high-glucose/hypoxia-induced damage to RPE cells and ameliorated retinal damage in diabetic mice. KLF10 is upregulated in DR model mice and high-glucose/hypoxia-exposed RPE cells and modulates apoptosis and ER stress through the PERK/eIF2α/ATF4/CHOP pathway. KLF10-IN-1 has protective effects, suggesting its potential for early DR treatment.

Lung adenocarcinoma remains one of the most common causes of cancer deaths. The tumor grows by avoiding the immune system and adapting to stress in the endoplasmic reticulum. The IRE1α-XBP1 pathway is a key pathway for cells to sense stress in the endoplasmic reticulum and has a large effect on the immune system. PRKCSH encodes a regulatory subunit of glucosidase II that helps keep the endoplasmic reticulum in balance by modifying how IRE1α works. However, it is unclear how it affects tumor immunity. This study used clinical sample analysis, bioinformatic analysis, CRISPR/Cas9-mediated gene deletion, cytokine profiling, macrophage co-culture, and zebrafish xenograft experiments to investigate the immunological role of PRKCSH. PRKCSH deficiency reduced basal IRE1α phosphorylation but led to exaggerated activation under ER stress, including increased XBP1s and p-JNK signaling. IL-6 and IL-8 secretion was suppressed in PRKCSH-knockout (KO) cancer cells, disrupting cytokine-mediated immune suppression. Conditioned media from PRKCSH-KO cells enhanced M1 macrophage polarization in vitro, as evidenced by increased CD86⁺ macrophages and expression of key M1-polarization markers. These effects were corroborated in zebrafish xenografts, where PRKCSH deficiency diverted the immune environment toward an M1-dominant phenotype. Analysis of clinical pleural effusion samples further validated these findings, revealing a significantly reduced M1/M2 macrophage ratio in malignant versus benign conditions. Furthermore, PRKCSH-KO cells exhibited increased susceptibility to ER stress-induced apoptosis and ferroptosis, along with impaired autophagy. In conclusion, our findings place PRKCSH as a key regulator linking ER stress signaling with tumor immune evasion and cell death pathways. Targeting PRKCSH may represent a promising therapeutic strategy to promote ferroptosis and anti-tumor immunity in lung adenocarcinoma.

Endoplasmic reticulum (ER) stress is a central adaptive response that maintains proteostasis under diverse metabolic and environmental challenges. In cancer, ER stress and lipid metabolism form a tightly coupled, bidirectional regulatory network that integrates protein quality control with lipid remodeling. Through the unfolded protein response (UPR), ER stress reprograms lipid synthesis, oxidation, and storage to sustain energy balance and membrane integrity. Conversely, dysregulated lipid accumulation disrupts ER homeostasis and amplifies stress signaling, creating a feedback loop between metabolic and proteostatic imbalance. Proteostasis systems, including the ubiquitin-proteasome system (UPS) and autophagy, cooperate with UPR signaling to fine-tune this adaptive balance and enhance tumor survival under stress. This review highlights the bidirectional crosstalk between ER stress and lipid metabolism from the perspective of proteostasis-driven tumor adaptation and summarizes emerging therapeutic strategies such as small-molecule modulators, natural products, and combination therapies that target this adaptive network to overcome drug resistance and improve cancer treatment.

BACKGROUND Neurodegeneration refers to the progressive loss of neurons, affecting both their structure and function. It is driven by synaptic dysfunction, disruptions in neural networks, and the accumulation of abnormal protein variants. Endoplasmic reticulum (ER) stress, caused by the accumulation of misfolded or unfolded protein, is a major contributor to neurodegeneration. Dithiothreitol (DTT) is a widely used redox reagent that disrupts the oxidative protein folding environment, inducing ER stress and leading to the imbalance in protein homeostasis can activate stress response pathway, potentially contributing to neurodegenerative processes. Caenorhabditis elegans (C. elegans ) is a widely used model organism for studying neurodegeneration due to its well-mapped nervous system, approximately one-third of neuron cells in their body, complete genome sequenced, and conserved stress response pathway. AIM To study the neurodegeneration in C. elegans caused by DTT-induced ER stress, assessed by behavioral, molecular, and lifespan changes. METHODS C. elegans were cultured on nematode growth medium plates with OP50, and ER stress was induced using DTT. Effects were assessed via behavioral assays such as locomotion, chemotaxis, lifespan assay, and molecular studies. RESULTS DTT exposure led to a significant decline in locomotion and chemotaxis response, indicating neurotoxicity. A reduction in lifespan was observed, suggesting an overall impact on health. Molecular analysis confirmed ER stress activation. DTT-induced ER stress negatively affects C. elegans , leading to behavioral impairments and molecular alterations associated with neurodegeneration. CONCLUSION These findings establish C. elegans as a potential model for studying ER stress-mediated neurotoxicity and its implications in neurodegenerative diseases.

A luciferase reporter gene assay demonstrates that a methanol extract of the aerial parts of Euphorbia lathyris L. activates reporter gene expression mediated by CCAAT-enhancer-binding protein homologous protein (CHOP) transcriptional activity in the human pancreatic cancer cell line MIA PaCa-2. We isolated 2 lathyrane-type diterpenoids, euphorbia factor L1 (EFL1) and L3 (EFL3), from the extracts. This is the first report of their isolation from aerial parts of this plant. Treatment of the MIA PaCa-2 with EFL1 or EFL3 increased the levels of phosphorylated inositol-requiring enzyme 1 alpha (IRE1α), activating transcription factor 4 (ATF4) and CHOP, involved in the endoplasmic reticulum (ER) stress pathway and cleaved poly (ADP-ribose) polymerase protein (PARP), as apoptotic markers, and inhibited cell proliferation. Thus, EFL1 and EFL3 may be useful in the development of treatments for pancreatic cancer.

ABSTRACTThe methylotrophic yeast Pichia pastoris (also known as Komagataella phaffii) is a prominent platform for recombinant protein production, offering benefits such as thermo‐ and osmotolerance, high‐density growth, and efficient protein secretion. Its ability to metabolise methanol, an increasingly available carbon source, enhances its cost‐effectiveness and sustainability for industrial use. As a eukaryotic host, P. pastoris ensures proper protein folding and post‐translational modifications (PTMs), including glycosylation, which is essential for correct folding and endoplasmic reticulum (ER) quality control. While ER‐transferred glycans are critical for maturation, additional modification in the Golgi apparatus can yield larger glycans whose impact on stability, solubility, and bioactivity may be either beneficial or undesirable, depending on the application of the heterologous protein. The impact of induction conditions on glycosylation of proteins secreted by P. pastoris SuperMan5 was examined, using the DS‐1 (G2P[4]) and WA (G1P[8]) VP8* rotavirus capsid proteins as a model. An ELISA‐based screening system was employed for clone selection and media optimization, with results showing easy integration into automated workflows. Methanol concentration was found to impact both N‐ and O‐linked glycosylation complexity, shaping the glycosylation profile of the target protein as well as the P. pastoris secretome. This study underscores the importance of optimising cultivation conditions to enhance protein yield, refine glycosylation, and minimise impurities, all of which are crucial for large‐scale production and efficient downstream processing. It also suggests a method for easy modulation of glycosylation depending on the target application and the desired level of glycosylation.

Placing a mustard oil bomb trigger in the endoplasmic reticulum: the SUN in plant defense against herbivory attack.

To explore novel biomarkers for clinical prognosis in patients with ovarian ageing, especially in premature ovarian insufficiency (POI). Prospective Cohort Study. Reproductive Hospital Affiliated with Shandong University, China. Sixty POI patients and 60 control women recruited from 2018 to 2019. Machine learning algorithms were used to screen features of ovarian ageing from public ovarian transcriptome data. The candidate serum biomarker, endoplasmic reticulum aminopeptidase-2 (ERAP2), was compared between 60 POI patients and 60 control women. A prospective follow-up of 4 years was conducted on POI patients, and prediction models were established for intermittent recovery of ovarian function and clinical pregnancy based on serum ERAP2 levels. Intermittent recovery of ovarian function and clinical pregnancy. Machine learning models identified ERAP2 as a novel biomarker associated with ovarian ageing. POI patients exhibited significantly elevated serum ERAP2 levels compared to controls (5.78 ± 2.29 ng/mL vs. 4.81 ± 2.20 ng/mL, p = 0.018). With a prospective follow-up of these POI patients, ERAP2 was found to be a new biomarker for predicting intermittent recovery of ovarian function (AUROC = 0.763, 95% CI 0.734-0.792) and clinical pregnancy (AUROC = 0.768, 95% CI 0.749-0.787). Integrating ERAP2 into existing indices significantly improved their prediction accuracy both in predicting intermittent recovery of ovarian function (IDI = 0.166, p = 0.008) and in clinical pregnancy (NRI = 0.442, p = 0.034; IDI = 0.208, p = 0.018). Serum ERAP2 can serve as a biomarker for intermittent recovery of ovarian function and clinical pregnancy in patients with POI. Combining ERAP2 with other clinical indicators may facilitate personalised intervention strategies for patients with POI in clinic.

Correction: Dietary phosphorus restriction induced phospholipid deficiency, endoplasmic reticulum stress, inflammatory response and gut microbiota disorders in Lateolabrax maculatus

Stimulator of IFN genes (STING) is an endoplasmic reticulum (ER) signaling receptor involved in the type I interferon response to pathogen- or self-derived cytosolic double-stranded DNA. Excessive activation of STING is associated with many diseases, but the regulatory mechanism of STING activation remains to be further elucidated. Here, we identify VAPB as a negative regulator of STING-mediated innate immune response. VAPB deficiency increases the expression of type I interferons under resting conditions or upon stimulation. Mechanistically, VAPB associates and translocates with STING, thereby regulating STING translocation, oligomerization, and recruitment of TBK1. In vivo, deficiency of VAPB enhances the expression of type I interferons and prevents lethality following HSV-1 infection. Furthermore, VAPB P56S, a pathogenic mutation causing amyotrophic lateral sclerosis (ALS), can promote STING-mediated innate immune response under resting conditions, which might contribute to further understanding of the relationship between cGAS-STING pathway and ALS. Our study identifies VAPB as a critical regulating factor in cGAS-STING–mediated innate immune responses.

Positive regulation of maize resistance to Bipolaris maydis by the cell death suppressor ZmDAD1.

B-cell receptor-associated protein 31 (BAP31), an endoplasmic reticulum (ER)-resident transmembrane protein, has emerged as a critical regulator of immune cell activation, yet its role in neuroinflammation remains unexplored. Here, we uncovered the natural compound neferine (Nef) as a pharmacological modulator of BAP31 that suppressed microglial activation. Using thermal protein profiling (TPP), we identified BAP31 as the primary target of Nef. Biochemical and structural analyses were employed to characterise Nef-BAP31 interactions. We evaluated ER stress and mitochondrial energy metabolism homeostasis using techniques such as STER super-resolution technology, flow cytometry, western blot, etc. In vivo validation utilised two models: lipopolysaccharide (LPS)-induced endotoxaemia and middle cerebral artery occlusion (MCAO) for ischaemic stroke, combining behavioural tests, cytokine profiling and histopathological assessments. Nef functioned as a 'molecular glue' by binding to BAP31's coiled-coil CC2 domain to induce stable dimerisation. We revealed that dimerised BAP31 triggered ER membrane remodelling, which disrupted ER-mitochondria contact sites and preserved mitochondrial energy metabolism homeostasis, thereby blocking inflammatory cytokine release. In vivo, Nef attenuated neuroinflammation in endotoxaemia mice and further conferred neuroprotection against ischaemic stroke in a MCAO model by inhibiting microglia-driven neuronal injury. In summary, our work reveals that BAP31 is a master regulator of ER-mitochondria communication during microglial activation and introduces a paradigm-shifting 'molecular glue' strategy for targeting ER-resident proteins. Additionally, these findings redefine the pharmacological landscape for modulating organelle interactions in microglia involved in neuroinflammatory diseases.

Establishment of γ-secretase-deficient goblet-like cells: A novel in vitro platform to dissect regulatory mechanisms of mucus production in the intestinal epithelium.

IP3R-dependent Ca2+ signaling in the endoplasmic reticulum is required for deoxynivalenol-induced intestinal stem cell injury.

An endoplasmic reticulum-targeting NIR fluorescent probe for monitoring the fluctuations of endogenous butyrylcholinesterase in live cells.

Endoplasmic reticulum stress as a nexus of temporomandibular joint osteoarthritis.

Temporal Regulation of Signal Recognition Particle During Translation.

Research note: duck Tembusu virus non-structural protein 3 induced autophagy through endoplasmic reticulum stress.

Impact of lead (Pb)-induced neurotoxicity on protein synthesis and cellular stress responses in LUHMES cells.

Mitochondrial MFN2 integrates the function of multiple organelles to regulate metabolic dysfunction-associated steatotic liver disease: mechanisms and therapeutic insights.