salubrinal / Soochow University - LARVOL DELTA

The effect of salubrinal on the endoplasmic reticulum stress pathway in heat-stressed spermatogonial cells in vitro. (PubMed, FEBS Open Bio) - "In light of these findings, we concluded that heat stress triggers ER stress in spermatogenic cells, and SAL might affect ER stress markers. Further studies on ER-related stress mechanisms in spermatogenic cells will be critical in developing therapeutic strategies with advanced molecular analyses in the future."

Journal • Preclinical • ATF6 • HSPA5

Radiotherapy-Related Autophagy Genes Predict Prognosis and Reveal Immunoscape Features and Immunotherapeutic Agents in Colorectal Cancer Patients. (PubMed, J Environ Pathol Toxicol Oncol) - "Medications such as CGP-082996, Dasatinib, Erlotinib, and Salubrinal were more sensitive to high-risk group, whereas drugs such as FTI-277, DMOG, and Crizotinib were more sensitive to low-risk group. UGT1A6 and IRGM were significantly upregulated in tumor group as revealed by qRT-PCR. This study constructed a new prognostic model for CRC patients based on RRAGs, and a series of analysis results is conducive to providing more theoretical references and new insights into precision treatment of CRC patients."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • UGT1A6

Rutin Suppresses EMT and Induces Mitochondrial Biogenesis via ER Stress-linked AMPK/SIRT1 Signaling in Prostate Cancer Cells. (PubMed, Cancer Genomics Proteomics) - "Rutin inhibits prostate cancer progression by suppressing EMT, inducing mitochondrial biogenesis, and acting via ER stress-linked AMPK/SIRT1 signaling. These findings suggest that Rutin may serve as a potential therapeutic candidate for advanced prostate cancer."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ATF6 • CDH1 • ERN1 • NRF1 • SNAI2 • TFAM

Regulation of the PERK pathway attenuates hypoxia-induced apoptosis in a 661W photoreceptor cell model. (PubMed, Exp Eye Res) - "Both Salubrinal (Sal) and PERK-targeting siRNAs (PERK-siRNAs) attenuated ER stress via the PERK/eIF2α/ATF4/CHOP pathway, reducing apoptosis and reactive oxygen species (ROS) production by suppressing HIF-1α...In a HAR mouse model under simulated 5,000 m altitude conditions, Sal improved retinal function, as evidenced by enhanced a- and b-wave amplitudes in electroretinogram (ERG) recordings. These findings suggest that ER stress modulation through PERK pathway inhibition mitigates hypoxia-induced retinal damage, highlighting its potential as a therapeutic strategy for HAR and related retinal disorders."

Journal • Ophthalmology • Retinal Disorders • ATF4 • HIF1A

Nuclear fragile X mental retardation-interacting protein 1-mediated ribophagy regulates immune function of dendritic cells in polymicrobial sepsis. (PubMed, Burns Trauma) - "Salubrinal, a specific inhibitor of EIF2A dephosphorylation, rescued dendritic cell dysfunction in septic mice with Nufip1 deficiency...These findings suggest that NUFIP1 regulates ER stress through the EIF2AK3-ATF4-damage-inducible transcript 3 pathway, highlighting its critical regulatory role in sepsis. Thus, NUFIP1 represents a new target for sepsis therapy."

Journal • CNS Disorders • Infectious Disease • Mental Retardation • Septic Shock • ATF4 • EIF2A • EIF2AK3 • EIF2S1 • ITGAX • PERK

The interaction between COX-2 and endoplasmic reticulum stress is involved in liver ischemia-reperfusion injury in mice. (PubMed, Mol Biol Rep) - "In mice with HIR, COX-2 interacts with ERS to cause liver injury by regulating oxidative stress and apoptosis."

Journal • Preclinical • Cardiovascular • Hepatology • Liver Failure • Reperfusion Injury • HSPA5 • PTGS2

Protective effects of Salubrinal against H2O2-induced muscle wasting via eIF2α/ATF4 signaling pathway. (PubMed, Front Pharmacol) - "Furthermore, salubrinal enhanced the expression of p-eIF2α and ATF4, suggesting that its protective effects are mediated through the eIF2α/ATF4 pathway. These findings highlight salubrinal's potential as a therapeutic agent for muscle wasting conditions, particularly those related to oxidative stress and ERS."

Journal • Muscular Atrophy • Sarcopenia • ATF4

Raphin-1 mediates the survival and sensitivity to radiation of pediatric-type diffuse high-grade glioma via phosphorylated eukaryotic initiation factor 2α-dependent and -independent processes. (PubMed, Mol Oncol) - "Inhibitors of phosphorylated eIF2α (PeIF2α) phosphatase-namely raphin-1 and salubrinal-decrease survival of PED-DHGG cell lines and sensitize them to radiation...Our results suggest that the sensitivity of PED-DHGG to raphin-1 is mediated by both PeIF2α-dependent and PeIF2α-independent processes. Elucidating these processes could reveal targets for the development of drugs to overcome radiotherapy resistance of PED-DHGG."

Journal • Brain Cancer • Glioma • High Grade Glioma • Oncology • Pediatrics • Solid Tumor

Inhibition of ER stress mitigates hypobaric hypoxia-induced retinal damage: a simulated high-altitude study. (PubMed, Neuroscience) - "Furthermore, via Transmission Electron Microscopy (TEM), Optical Coherence Tomography (OCT), Hematoxylin and Eosin (H&E) staining, and Electroretinography (ERG), we confirmed that Salubrinal could alleviate hypobaric hypoxia-induced retinal edema and enhance retinal function by inhibiting the ER stress level of the PERK/eIF2α/ATF4/CHOP pathway in HAR mice. Our findings indicate that targeting the ER stress PERK pathway may be a promising therapeutic approach for managing HAR, offering potential clinical implications for treating this altitude-related ocular disorder."

Journal • Ophthalmology • Retinal Disorders • ATF4

PERK-mediated eIF2α phosphorylation suppresses porcine epidemic diarrhea virus replication by attenuating global protein synthesis and inducing IFN-Ⅰ production. (PubMed, Vet Microbiol) - "The PERK-eIF2α pathway inducers CCT020312 and salubrinal efficiently inhibited the replication of multiple genotypes of PEDV in both Vero and ST cells, whereas the inhibitor AMG PERK 44 promoted PEDV replication...Additionally, phosphorylated eIF2α promotes NF-κB signaling activation and facilitates to the production of IFN-Ⅰ, eliciting innate immunity to suppress viral replication. These data show that PERK-eIF2α pathway dampens the replication of multiple genotypes of PEDV, suggesting that this target may be exploited to develop as a broad-spectrum anti-PEDV drugs."

Journal • Preclinical • MAPK4

Mechanistic Insights into the Plasmodium Phosphatase UIS2 in eIF2α Dephosphorylation via Integrated Structure-Based Modeling. (PubMed, bioRxiv) - "Metadynamics simulations show that the inhibitor Salubrinal competes with the phosphopeptide for binding to this pocket...These findings show the structural and energetic basis of eIF2α dephosphorylation by UIS2. They provide an integrated modeling approach for phosphatase-substrate interactions and a mechanistic rationale for selective inhibition of a parasite-specific translation regulator."

Journal • Infectious Disease

Mitochondrial Reactive Oxygen Species and Endoplasmic Reticulum Stress in Hyperoxia-induced Senescence in Developing Human Airway Smooth Muscle (ATS 2025) - " fASM isolated from lungs of 18-20 week aborted fetuses (Mayo IRB exempt; period of rapid bronchial airway growth) were exposed to normoxia, hyperoxia or etoposide (10 µM; positive control for senescence induction). Hyperoxia induces senescence in fASM via mitochondrial ROS and ER stress: pathways that offer new opportunities to blunt detrimental effects of oxygen in developing lung via mitochondrial targeted antioxidants and/or ER stress inhibition."

Asthma • Bronchopulmonary Dysplasia • Immunology • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • ATF6 • CAV1 • CDKN1A • LMNB1 • PPP1R15A

Effect of endoplasmic reticulum stress on bone and cartilage growth via endochondral ossification in broilers. (PubMed, J Anim Sci) - "Salubrinal (SAL), an ERS inhibitor, was administrated to explore its effects on bone disorders...Overall, this study highlights the negative effects of wire flooring on bone and cartilage, which are closely related to the occurrence of bone disease. Additionally, it suggests that blocking ERS may protect broilers from poor flooring conditions by regulating EO."

Journal • Orthopedics

Construction of a risk model associated with tryptophan metabolism and identification of related molecular subtypes in laryngeal squamous cell carcinoma. (PubMed, Front Genet) - "Besides, the drug sensitivity analysis showed that the low -risk subgroup was notably sensitive to Salubrinal, Lenalidomide, Metformin, while high -risk subgroup was more responsive to Docetaxel, AUY922, Embelin. Eventually, two clusters of LSCC samples had notable correlations with LSCC prognosis. The above results indicated that the risk model consisted of TMRGs (SERPINA1, TMC8, RENBP, SDS and FAM107A) was constructed in LSCC, contributing to studies related to the prognosis and treatment of LSCC."

IO biomarker • Journal • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • SERPINA1

Hyperoxia-induced senescence in fetal airway smooth muscle cells: Role of mitochondrial reactive oxygen species and endoplasmic reticulum stress. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "However, the level of p21 and/or Bcl-xL was decreased in hyperoxia-exposed cells treated with the ER stress inhibitor salubrinal or the antioxidant MitoQ, but not the fission inhibitor Mdivi-1. These findings highlight the role of mitochondrial ROS and ER stress in hyperoxia-induced senescence of fASM and suggest that via mitochondrial targeted antioxidants and/or inhibitors of ER stress pathways can blunt the detrimental effects of hyperoxia in developing lung."

Journal • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • BCL2L1 • CDKN1A

Cannabinoids Activate Endoplasmic Reticulum Stress Response and Promote the Death of Avian Retinal Müller Cells in Culture. (PubMed, Brain Sci) - "These data suggest that cannabinoids induce the apoptosis of glial cells in culture by promoting ROS production, ER stress, JNK phosphorylation, and caspase-3 processing. The graphical abstract was created at Biorender.com."

Journal • CASP3

Outer radial glia promotes white matter regeneration after neonatal brain injury. (PubMed, Cell Rep Med) - "Intranasal activation of ATF5 using salubrinal enhanced OSVZ-derived oligodendrogenesis in the injured periventricular white matter and improved functional recovery. These results reveal a key role for postnatal oRG in brain injury recovery and identify ATF5 as a potential therapeutic target for treating white matter injury in infants."

Journal • CNS Disorders • Solid Tumor • Vascular Neurology • ATF5

Interleukin-36β inhibits CD4+CD25+ regulatory T cells by activating endoplasmic reticulum-phagy in septic mice. (PubMed, Int Immunopharmacol) - "IL-36β can down-regulate the immune activity of CD4+CD25+ Tregs via ER-phagy induction. Our study might provide novel targets for therapeutic strategies to prevent the development of sepsis."

Journal • Preclinical • Infectious Disease • Septic Shock • ATF4 • CD4 • IL2RA • TCF4

Downregulation of HSP47 triggers ER stress-mediated apoptosis of hypertrophic chondrocytes contributing to T-2 toxin-induced cartilage damage. (PubMed, Environ Pollut) - "Treatment with the ER stress inhibitor Salubrinal suppressed the upregulation of caspase-3 activity, BiP, caspase-12, and CHOP while partially restoring HSP47 expression in T-2 toxin-treated hypertrophic ATDC5 chondrocytes...Downregulation of HSP47 leads to ER stress-mediated apoptosis in T-2 toxin-induced cartilage damage. Inhibition of ER stress offers a potential therapeutic approach for mitigating T-2 toxin-induced cartilage damage."

Journal • CASP1 • CASP12 • CASP3 • HSPA5 • SERPINH1

SEC62-dependent ER-phagy contributes to apelin-13/APJ-induced monocyte-vascular endothelial cell adhesion in atherosclerosis pathogenesis. (PubMed, Acta Pharmacol Sin) - "This effect was reversed by autophagy inhibitor 3MA (10 mM) and endoplasmic reticulum stress inhibitor salubrinal (10 μM)...We conclude that apelin-13 induces SEC62-dependent ER-phagy to promote monocyte-endothelial cell adhesion and atherosclerosis. This study reveals new mechanisms underlying atherosclerosis and identifies a potential therapeutic target."

Journal • Atherosclerosis • Cardiovascular • Targeted Protein Degradation • APOE • UBL4A

Repressing cytokine storm-like response in macrophages by targeting the eIF2α-integrated stress response pathway. (PubMed, Int Immunopharmacol) - "Here we carried out a proof-of-concept study, employing two approaches: (1) ectopic expression of the eIF2α-S51D mutant (mimicking the phosphorylated eIF2α); (2) treatment with salubrinal, a small molecule inhibitor of eIF2α dephosphorylation...Our data suggest that direct manipulation of eIF2α phosphorylation, thereby bypassing all associated upstream signaling events, may suppress the cytokine storm-like response in activated macrophages, likely by decoupling the gene transcription and protein translation. Inhibiting eIF2α dephosphorylation with small molecule inhibitors may be a viable therapeutic strategy to treat disorders involving cytokine storm-like responses."

IO biomarker • Journal • Acute Lung Injury • Inflammation • Respiratory Diseases • mTOR • PPP1R15A • TLR4 • TNFA

Zinc Transporter 9 (ZnT9) Improves Obesity-Induced Asthenospermia by Attenuating Endoplasmic Reticulum Stress (ERS). (PubMed, Biol Trace Elem Res) - "In addition to the HFD, a 5-week intervention of salubrinal (SAL) (an inhibitor of endoplasmic reticulum stress) (1 mg/kg/day), ZnSO4 (15 mg/kg/day), and their combination was started at week 6, after which sperm viability and epididymal tissue damage were assessed...According to this study, obesity leads to elevated ERS and affects ZnT9 protein synthesis. Inhibition of the Wnt pathway ultimately leads to cell death and damage in epididymal tissue and decreased sperm viability."

Journal • Genetic Disorders • Obesity • BAX • CASP3 • CTNNB1 • HSPA5

Peptide amphiphiles alleviate myocardial endoplasmic reticulum stress to enhance cardiomyocyte-macrophage communication and promote macrophage M2 polarization. (PubMed, J Control Release) - "In this study, we developed a cascade-responsive drug delivery system, CT-PA@Sal, which selectively targets damaged cardiomyocytes and controls the release of the ER stress inhibitor Salubrinal...These effects preserve cardiac function and enhance tissue recovery following I/R injury. We envision that this investigation offers a prospective framework for developing targeted drugs to treat myocardial I/R injury."

Journal • Cardiovascular • Myocardial Ischemia • Reperfusion Injury

Integrated stress response-upregulated mitochondrial SLC1A5var enhances glucose dependency of human breast cancer cells (SABCS 2024) - "Our investigation indicated that activating transcription factor-4 (ATF4), triggered by glucose depletion, oligomycin (an inhibitor of mitochondrial ATP synthase), and salubrinal (an ISR activator) stimulation, induces the expression of SLC1A5var...These findings suggest that ISR-activated upregulation of SLC1A5var potentially modulates mitochondrial oxidative phosphorylation and glycolysis characteristics to augment glucose depletion-induced cell death. In conclusion, SLC1A5var plays a pivotal role in the metabolic reprogramming process and may represent a promising target for breast cancer therapy."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ATF4 • SLC1A5 • SLC7A11 • TCF4

The Therapeutic Potential of Salubrinal on the Pathophysiology of MECFS and Long COVID (ASHP 2024) - No abstract available

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