Abstract Background The aim of this study was to evaluate the genetic polymorphism of glucose-regulated protein 78 (GRP78) in acute invasive fungal sinusitis (AIFS) patients with analysis of risk factors and disease outcomes. Methods In this study, 20 controls and 20 patients were enrolled. Venous blood was taken from the patient and control groups. Extraction of the genetic material followed by genotyping of GRP78 rs 391957 and GRP78 rs 430397 polymorphisms was performed using restricted fragmentation length polymorphism (RFLP) genotyping assays. The different polymorphisms of GRP78 rs 391957 (CC, CT, TT) and GRP78 rs 430397 (GG, GA, AA) alleles were obtained and compared between patients and control and compared within patients’ group to the disease risk factor, morbidity, and mortality. Results The expression of genotype alleles GRP78 GA rs430397 and GRP 78 TT rs391957 was higher in AIFS patients than in the control group. There was a significant increase in genotype GA rs430397 in hyperglycemic patients and increase in genotype GG rs430397 in neutropenic patients. There was a statistically significant increase in GA genotype rs430397 in advanced stages of disease and also increase in the same genotypes in patients that underwent open debridement or died from the disease. Conclusion The alteration of expression of GRP78 rs 430397 genes may be related to the development of AIFS. Furthermore, genotype GA rs430397 GRP78 is related to hyperglycemia, orbital, cranial involvement, the need for open surgical debridement, and mortality from acute invasive fungal sinusitis.

Inter-organelle communication via membrane contact sites (MCSs) is essential for the efficient functioning of eukaryotic cells, facilitating coordination among approximately 20 distinct organelles, each with unique metabolic profiles. Among these interactions, mitochondria-endoplasmic reticulum (ER) contacts (MERCs) are particularly significant, encompassing about 5% of the mitochondrial surface. Key proteins involved in MERCs include inositol 1,4,5-trisphosphate receptor (IP3R), voltage-dependent anion channel (VDAC), glucose-regulated protein 75 (GRP75), Sigma1 receptor (Sig-1R), vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), protein deglycase DJ-1, and protein tyrosine phosphatase interacting protein 51 (PTPIP51), with new proteins continually being identified for their roles in these structures. At these contact sites, metabolic exchanges involve calcium (Ca2+), lipids, reactive oxygen species (ROS), and proteins. MERCs enable efficient molecular exchanges through temporary bridges mainly formed by the ER, the organelle with the largest surface area. These contacts are crucial for maintaining mitochondrial dynamics, which is essential for cellular homeostasis, and they are notably impacted in pathological states such as metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver diseases (ALD), and viral hepatitis. Dysfunctional MERCs can lead to mitochondrial fragmentation, increased ROS production, impaired autophagy, and disrupted protein trafficking, thereby exacerbating senescence and cellular aging. Senescence is a cell fate initiated by stress, characterized by stable cell-cycle arrest and a hypersecretory state, and is an underlying cause of aging and many chronic conditions, including liver diseases. The hallmarks of senescence-such as macromolecular damage, cell cycle withdrawal, deregulated metabolism, and a secretory phenotype-are well established. However, recent studies have demonstrated that senescence is a heterogeneous process, with molecular markers varying according to the stressors that induce it. This review focuses on the functional aspects of MERCs in hepatic senescence and their impact on liver diseases, and explores the potential of targeting MERCs to address hepatocytic senescence.

About 20% of breast cancer cases are triple-negative breast cancer (TNBC), a highly aggressive subtype with limited therapeutic options. Emerging evidence suggests that ferroptosis — a form of regulated cell death — and stress-response pathways play critical roles in TNBC progression. We investigated the interaction between glucose-regulated protein 78 (GRP78), a central stress-response chaperone, and mitochondrial glutathione peroxidase 4 (mGPX4), a key regulator of ferroptosis resistance. Using a combined computational approach — including protein–protein docking, molecular dynamics (MD) simulations, and MM/GBSA free-energy calculations — we identified stable complexes between GRP78’s SBDβ domain and several regions of mGPX4. Docking with PRODIGY revealed binding affinities ranging from − 7.7 ± 0.5 to − 10.5 ± 0.6 kcal/mol, surpassing that of Pep42 (–6.9 ± 0.1 kcal/mol), with region III (the mitochondrial import sequence) showing the strongest binding (–10.5 ± 0.6 kcal/mol). HADDOCK scoring further highlighted region II as particularly favorable (–72.0 ± 5.4). After 100 ns of MD, MM/GBSA analysis estimated binding free energies from − 45.20 to − 86.39 kcal/mol, with the region-II complex exhibiting the highest affinity (–86.4 kcal/mol), driven predominantly by electrostatic and van der Waals interactions. This interaction could serve as a promising therapeutic target to undermine cancer cell survival by sensitizing TNBC cells to ferroptosis-inducing strategies.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-33108-1.

Inhibition of cell surface GRP78 on brain tumors reverses drug resistance and stops cancer stem cell expansion.

Deficiency of Mesencephalic Astrocyte-Derived Neurotrophic Factor Aggravates Acute Pancreatitis in Mice.

Repetitive traumatic brain injury (RTBI) refers to brain injuries resulting from an external mechanical force causing cumulative and frequently severe neurological consequences. This study aimed to explore the neuroprotective effect of alogliptin (ALO) on RTBI-provoked endoplasmic reticulum (ER) stress and investigate the potential underlying mechanisms. For RTBI induction, rats were exposed to a sharp-edged weight at the right interior frontal area of the right cortex, one drop per day for five successive days. ALO (20 mg/kg/day, p.o.) was administered for one week. Results depicted that ALO recovered motor abnormalities and enhanced motor coordination in the open field test, decreased immobility and increased climbing time in the forced swimming test, and corrected histological aberrations. Moreover, ALO counteracted RTBI-triggered ER stress via suppression of activating transcription factor 6 (ATF6), glucose-regulated protein 78 (GRP78), aggregation of β-amyloid and Tau proteins, as well as elevation of the cortical content of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrKB). ALO also exhibited an antioxidant and anti-inflammatory potential in addition to its effect on the gene expression of miRNAs (miRNA-322 and miRNA-125b). In conclusion, ALO exhibited a neuroprotective effect by mitigating ER stress induced in an RTBI rat model. Graphical Supplementary InformationThe online version contains supplementary material available at 10.1007/s11481-025-10271-w.

Dietary phospholipids alleviate high fat diet-induced intestinal lipid deposition through ATF4-PPARα-MTTP/SAR1B pathway in yellow catfish.

Overexpression of peroxiredoxin 6 in bone marrow-derived mesenchymal stem cells amplifies their in vivo effect on bronchopulmonary dysplasia by increasing mesencephalic astrocyte-derived neurotrophic factor secretion.

Polycyclic aromatic hydrocarbons-enriched diesel exhaust particles induced hypertrophy in rat primary neonatal cardiomyocytes and apoptotic cell death in H9c2 cardiomyocytes.

Waterborne trace elements (TE), such as mercury (Hg) and zinc (Zn), are environmental contaminants that often co-occur in aquatic ecosystems. Cucurbita pepo (pumpkin peel; PP) is a medicinal plant with diverse pharmacological properties. Accordingly, this innovative trial looked at the efficacy of PP, administered as powder (12.00g/kg diet), in mitigating the toxicological effects of a mixture of trace elements (MTE) containing Hg (0.05mg/L) and Zn (7.00mg/L) in Oreochromis niloticus. A total of 160 fingerlings (28.50 ± 1.33g) were randomly assigned to four groups, with four replicates per group: control, PP, MTE, and PP + MTE. The experiment was conducted over two months. The findings disclosed a reduced fish survival rate (72.50%) and a pronounced neuro-stress response following MTE exposure, as indicated by elevated cortisol, norepinephrine, and glucose concentrations, along with decreased acetylcholinesterase activity. The MTE exposure also induced oxidative stress in gills, evidenced by increased malondialdehyde concentration and diminished glutathione peroxidase activity, and reduced glutathione content. Additionally, MTE caused extensive histopathological alterations in both brain and gill tissues. Furthermore, MTE exposure induced endoplasmic reticulum stress and activated apoptotic pathways, as evidenced by the significant upregulation of cysteine-aspartic acid protease-3 (casp-3), eukaryotic translation initiation factor 2A (eif-2a), C/EBP homologous protein (chop), and X-box binding protein 1(xbp-1) and inositol-requiring enzyme 1 alpha (ire-1α), activating transcription factor 6 (atf-6), and glucose-regulated protein 78 (grp-78) genes in both the brain and gills. Remarkably, dietary supplementation with PP improved these parameters and restored normal tissue histology. These findings suggest that PP can be effectively incorporated into the diet of O. niloticus to mitigate the toxic effects of MTE exposure.

Neuroblastoma (NB), the most common extracranial solid tumor in children, remains challenging to treat due to limited therapeutic efficacy and poor prognosis. Emerging evidence highlights the critical roles of endoplasmic reticulum (ER) stress and autophagy in cancer progression. The present study investigated the therapeutic potential of melatonin in neuroblastoma and its underlying mechanisms. Using Neuro‑2a (N2a) cells, it demonstrated that melatonin alleviated ER stress by upregulating ER chaperones glucose‑regulated protein (GRP)78 and GRP94 and the pro‑apoptotic protein CHOP, while enhancing autophagic activity. Western blotting revealed increased LC3‑II/I ratios, elevated autophagy‑related protein 5 and Beclin1 levels, and reduced p62 expression, indicating autophagy induction. Immunofluorescence and transmission electron microscopy confirmed the dose‑dependent accumulation of autophagosomes. ER stress inhibitor 4‑phenylbutyric acid attenuated melatonin‑induced autophagy, linking ER stress relief to autophagic activation. Mechanistically, melatonin upregulated p21‑activated kinase 2 (Pak2), which suppressed mTOR phosphorylation and activated unc‑51‑like kinase 1, thereby modulating the AMP‑activated protein kinase (AMPK) pathway. Pak2 overexpression amplified melatonin's ER stress‑alleviating effects, whereas Pak2 knockdown or AMPK inhibition diminished its efficacy. These findings established that melatonin suppresses neuroblastoma growth by mitigating Pak2‑mediated ER stress to induce cytotoxic autophagy. The present study provided novel insights into melatonin as a promising therapeutic agent for neuroblastoma, warranting further exploration in preclinical models and clinical trials.

Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER-2 amplification, rendering it unresponsive to endocrine and HER2-targeted therapies. GRP78 (78 kDa glucose-regulated protein), a key endoplasmic reticulum (ER)-resident chaperone involved in protein folding and stress response, has been observed atypically localized on the cell surface of various cancer and stressed cell types, where it engages in non-canonical signaling and cellular functions. Cell surface GRP78 (csGRP78) is preferentially expressed in malignant cells relative to normal tissue, making it an attractive therapeutic target. In this study, we report that over 70% of MDA-MB-231 TNBC cells express csGRP78. Interestingly, MDA-MB-231 cells predominantly exhibit a distinct unipolar morphology, with csGRP78 prominently co-localizing with the variant isoform of CD44 (CD44v, containing variable exon 3) at the anterior region of the cell. Co-localizations of csGRP78 and CD44v were also observed in MDA-MB-231 tumor xenografts, supporting its relevance in vivo. Importantly, targeting csGRP78 with the monoclonal antibody 76-E6 downregulated CD44v expression, inhibited Src kinase signaling, disrupted cell morphology, and suppressed cell motility. We further mapped the epitope of GRP78 targeted by 76-E6. Together, our findings identify csGRP78 as a functional regulator of cell morphology and migration at least in part via a csGRP78-CD44v axis and underscore its potential as a therapeutic target in TNBC.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-33441-5.

IntroductionThe coronavirus disease 2019 (COVID-19) pandemic underscored the urgent need for broad-spectrum antiviral agents capable of targeting both viral proteins and host factors to mitigate disease severity. Apigenin has antiviral and anti-inflammatory properties. However, the potential of apigenin against SARS-CoV-2 remains insufficiently explored.MethodsIn this study, the potential role of apigenin in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the underlying mechanism were explored using matrix factorization, deep learning, multiscale molecular modeling and network pharmacology.ResultsThe graph-based integrated Gaussian kernel similarity (GiGs) model predicted that apigenin might be a drug against SARS-CoV-2. The prediction of drug-target affinity using a convolution model with self-attention (CSatDTA) model revealed the potential binding affinity of apigenin with glucose-regulated protein 78 (GRP78) and heparan sulfate proteoglycan (HSPG). Molecular docking further validated strong binding to GRP78 (–8.198 kcal/mol) and moderate binding to HSPG (–5.6 kcal/mol), mediated by van der Waals forces and hydrogen bonds. Multiscale molecular modeling revealed that apigenin could bind to Non-structural protein 15 (Nsp15). Further, the network pharmacology analysis implied that apigenin might modulate the host inflammatory responses by potentially regulating the PI3K-Akt and HIF-1 signaling pathways and binding directly to protein kinase B (AKT1) and prostaglandin endoperoxide synthase 2 (PTGS2).DiscussionComputational profiling suggests apigenin exerts a multi-target mechanism against SARS-CoV-2, potentially disrupting viral entry, replication, and host inflammatory responses. The findings of this research outline a promising strategy and provide a rationale for developing novel natural product-based treatment methods for SARS-CoV-2.

Arachidonic acid (AA), an omega-6 polyunsaturated fatty acid, is abundant in animal-derived food and is widely present in phospholipids of plasma membrane. Recent studies reported that ethanol exposure leads to the activation of prostaglandin signaling via increasing the levels of AA and its metabolites in cardiomyocytes. To test the hypothesis that AA contributes at least in part, to ethanol-induced cardiomyocyte injury, a chronic ethanol feeding model was used, in which male Wistar rats were fed Lieber-Decarli ethanol diet 6.7% (v/v) or isocaloric control diet for 6 weeks. Gas chromatography analysis indicated that ethanol exposure increased the AA content in rat myocardial phospholipids along with increased protein levels of endoplasmic reticulum (ER) stress markers and a decrease in the level of NADH: ubiquinone oxidoreductase subunit B8, a mitochondrial complex I subunit. In addition, an in vitro model was used in which H9c2 cells, a rat cardiomyoblast cell line, were exposed to AA and/or ethanol (ET), and markers of steatosis and endoplasmic reticulum stress, and mitochondrial respiration were assessed. Of note, AA supplementation potentiated ethanol-induced steatosis. H9c2 cells receiving ET + AA showed an increase in the expression of ER stress markers, including glucose-regulated protein 78 and activating transcription factor 4, compared with controls. Interestingly, compared to ET treatment, ET + AA treatment led to a significant decrease in basal respiration and ATP-linked respiration, indicating an impaired mitochondrial respiration in H9c2 cardiomyoblasts. Finally, inhibiting long-chain acyl CoA synthases by Triacsin C attenuated ET + AA treatment-induced steatosis but increased mitochondrial respiration in H9c2 cells. Collectively, these data suggested that AA supplementation promotes ethanol-induced steatosis and endoplasmic reticulum stress with a concomitant impairment in mitochondrial respiration in H9c2 cardiomyoblasts, and Triacsin C treatment inhibits steatosis but enhances mitochondrial respiration possibly via altered fatty acid partitioning between synthetic and oxidative processes.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12944-025-02792-3.

Computational characterization of HIV envelope interactions with cellular GRP78 as a potential entry mechanism.

Targeting TDP-43-activated GRP78/endoplasmic reticulum stress axis suppresses triple-negative breast cancer progression.

The endangered cold-water fishBrachymystax tsinlingensis(B. tsinlingensis) serves as a critical sentinel species for aquatic ecosystem responses to climate change. This study investigates heat stress impacts on behavior, physiology, and molecular homeostasis in B. tsinlingensis, and evaluates neuroprotective effects of anti-stress additives (vitamin C, gamma-aminobutyric acid, trehalose). Behavioral analysis showed a significant increase in center-zone entries under heat stress. Physiological assays showed a reduction in superoxide dismutase (SOD) and catalase (CAT) activities, alongside an upregulation of heat shock protein 70 (Hsp70), glucose-regulated protein 78 (GRP78), andcaspase expression under heat stress, with a return to baseline levels following a 12 h recovery. For assays in the brain, histopathological examination identified vacuolation in cerebral tissue after heat stress. Quantitative proteomics analysis identified 831 differentially expressed proteins (DEPs) out of 8,955 proteins during the temperature change process. Pathway analysis revealed that the 'DNA replication' and 'Citrate cycle' pathways were inhibited by heat stress but reactivated during recovery, whereas the 'ECM-receptor interaction' and 'Cell adhesion molecules' pathways exhibited opposite trends. Intervention with additives showed that trehalose enhanced SOD, glutathione peroxidase (GPX), and CAT activities, as well as gene expression related to cell adhesion and barrier function. Gamma-aminobutyric acid maximally suppressed stress-related genes (Hsp70, long-chain-fatty-acid-CoA ligase, and arachidonate lipoxygenase), while vitamin C exhibited general but less targeted effects. As the first proteomic study on B. tsinlingensis, this work reveals that blood-brain barrier reconstruction and energy reallocation are key neural survival strategies under temperature change stress. Furthermore, trehalose demonstrates high potential as an anti-heat stress additive by enhancing both antioxidant defenses and blood-brain barrier integrity. These findings advance our understanding of heat adaptation mechanisms in cold-water fish species and provide scientific foundations for conserving B. tsinlingensis.

Trehalose supplementation ameliorates heat stress-induced intestinal barrier dysfunction by suppressing endoplasmic reticulum stress and modulating gut microbiota in mice.

Soybean glycinin and β-conglycinin disrupted mitochondria-endoplasmic reticulum interactions in porcine intestinal epithelial cells via oxidative stress cascades.

Melatonin alleviates Di-2-ethylhexyl phthalate induced male reproductive toxicity through inhibition of endoplasmic reticulum stress: Behavioral, biochemical, and morphological evidences.