GSK2606414 / GSK, Institute of Cancer Research, Dartmouth College - LARVOL DELTA

A Potentially Protective Role for NRF2 in Endocannabinoid-Mediated Oxidative Stress in Human Coronary Artery Endothelial Cells. (PubMed, Cell Biochem Biophys) - "Likewise, the PERK inhibitor GSK2606414 prevented NRF2 induction by anandamide and tunicamycin while treatment with Ceapin A7 (an ATF6 inhibitor) or GSK2850163 (an IRE1α inhibitor) did not. In conclusion, endocannabinoid-related ER stress increased superoxide generation accompanied by compensatory increase in production of antioxidant enzymes thereby highlighting the cross talk between ER stress and oxidative stress."

Journal • Cardiovascular • CNS Disorders • ATF6 • ERN1 • HMOX1 • NQO1 • PERK

TMEM97 links endoplasmic reticulum stress to hepatic stellate cell activation in experimental liver fibrosis: pharmacological attenuation by CT1812. (PubMed, Eur J Pharmacol) - "Human LX-2 cells were stimulated with transforming growth factor-β1 (TGF-β1) and treated with TMEM97-targeting small interfering RNA (siTMEM97), CT1812, or both; confirmatory experiments used a second siRNA and GSK2606414. In vivo, CT1812 reduced hepatic hydroxyproline accumulation, collagen staining, α-SMA and collagen I expression, ER-stress markers, liver-injury indices, inflammatory cytokines, and macrophage accumulation. These findings support TMEM97-associated σ-2 receptor complex signaling as a contributor to ER-stress-coupled HSC activation and identify CT1812 as a candidate pharmacological modulator of experimental liver fibrosis."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • ACTA2 • ATF4 • ATF6 • COL1A1 • CTGF • ER • ERN1 • TGFB1

Trigeminal Nerve Electrical Stimulation Attenuates Hypoxic-Ischemic Brain Injury by Regulating GLT-1-mediated Endoplasmic Reticulum Stress. (PubMed, Brain Res Bull) - "TNS protects against neonatal hypoxic-ischemic brain injury by enhancing hippocampal GLT-1 expression and suppressing ERS-mediated neuronal injury. These findings identify TNS as a promising neuromodulatory strategy for neonatal HIBD and provide new mechanistic insights into its neuroprotective effects."

Journal • CNS Disorders • Vascular Neurology • ATF4 • HSPA5

Quercetin alleviates high fluoride-induced hepatocyte ferroptosis via regulating the ROS/PERK signaling pathway. (PubMed, Ecotoxicol Environ Saf) - "Pharmacological intervention assays verified that PERK inhibitor GSK2606414 mimicked Que's anti-ferroptotic effects, whereas PERK agonist CCT abolished Que-mediated protection against NaF-induced ferroptosis. Importantly, ROS elimination by N-acetylcysteine suppressed PERK activation and subsequent ferroptosis triggered by NaF. Overall, Que mitigates NaF-induced hepatic ferroptosis via inhibiting the ROS/PERK signaling pathway, highlighting its potential therapeutic application against high fluoride-induced hepatotoxicity."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hepatology • Inflammation • Liver Failure • ACSL4 • GPX4

Mechanical ventilation activates PERK/eIF2α and NOD1 pathways that contribute to NF-κB-driven inflammation in VILI. (PubMed, Respir Res) - "HTV-induced inflammatory lung injury is associated with activation of both NOD1 and PERK/eIF2α signaling. Mechanistically, these pathways contribute to NF-κB-associated inflammatory responses and lung injury in VILI. Notably, the greater protection observed under combined NOD1 deficiency and PERK inhibition, despite a plateau in NF-κB readouts, suggests that additional injury mechanisms beyond NF-κB may also be involved."

Journal • Inflammation • Respiratory Diseases • HSPA5 • IL1B • IL6 • NOD1 • TNFA

Endoplasmic Reticulum Is A Master Regulator of Cellular Stress (ENDO 2026) - "Treatment of HCAEC with the ER stress inducers tunicamycin and thapsigargin increased SO generation after 24 hours; these effects were suppressed by alpha-tocopherol and ascorbic acid, and by the ER stress inhibitors 4-phenylbutyrate and tauroursodeoxycholic acid. The increased oxidative stress in cells treated with tunicamycin and thapsigargin, was associated with increased secretion of inflammatory cytokines notably TNFalpha, IL-1beta, IL-6, and IL-8, but not IL-2, while amelioration of ER stress with GSK2850163 [an inositol requiring enzyme 1alpha (IRE1alpha inhibitor] and GSK2606414 [a protein kinase R-like endoplasmic reticulum kinase (PERK) inhibitor], but not Ceapin A7 [an activating transcription factor 6 (ATF6 inhibitor)], normalized inflammatory cytokine release...Overall, it appears that inflammatory stress can be the result of oxidative stress and ER stress and the latter effect could be a direct or indirect effect through ER instigated oxidative stress...."

Cardiovascular • ATF6 • CXCL8 • ERN1 • IL1B • IL2 • IL6 • PERK • TNFA

A Protective Role for Endocannabinoids in Preventing Oxidative Stress in HCAEC (ENDO 2026) - "Likewise, the PERK inhibitor GSK2606414 prevented NRF2 induction by anandamide and tunicamycin while treatment with Ceapin A7 (an ATF6 inhibitor) or GSK2850163 (an IRE1alpha inhibitor) did not. In conclusion, endocannabinoid related ER stress augments production of antioxidant enzymes thereby highlighting the cross talk between ER stress and oxidative stress."

Oxidative stress • Cardiovascular • CNS Disorders • ATF6 • ERN1 • HMOX1 • NQO1 • PERK

Endometrial Stromal ER Stress Transmission Reshapes Dendritic Cell Phenotype and Alters Trophoblast Behavior through IRE1α Signaling (ASRI 2026) - "Based on these findings, we sought to identify the specific UPR branches mediating the effects of ERS transmission on DC immunoregulatory function.Methods of study: Human endometrial stromal cell line (HESC) was exposed to thapsigargin (Tg) to induce exacerbated ERS, with or without prior treatment with IRE1α (STF-083010) or PERK (GSK2606414) inhibitors. Collectively, these findings reveal a previously unrecognized stromal-immune communication pathway driven by IRE1α-dependent ERS transmission, which exerts a profound influence on DC differentiation, inflammatory profile, and viability, in turn impacting trophoblast behaviour. A more profound comprehension of the underlying mechanisms and the discrete UPR branches implicated may facilitate the development of more precise strategies to mitigate excessive ER stress, with the potential to enhance current therapeutic interventions for pregnancy complications associated with sterile inflammation."

Stroma • Inflammation • ANXA5 • CD83 • CD86 • IL1B

Genomic insights into the tunicamycin-induced endoplasmic reticulum stress response in peripheral blood mononuclear cells: A comprehensive RNA sequencing analysis. (PubMed, Biochem Biophys Rep) - "In this study, we used next-generation RNA sequencing to profile transcriptional changes in peripheral blood mononuclear cells (PBMCs) after 24 h of tunicamycin exposure, alone or with the PERK inhibitor GSK2606414 or the eIF2B activator ISRIB, to assess stress responses at distinct regulatory points within the PERK-ISR pathway...Pathway enrichment analysis revealed overrepresentation of pathways related to ER stress responses, unfolded protein homeostasis, ER chaperone complex assembly, amino acid biosynthesis and interconversion, and aminoacyl-tRNA synthetase-mediated protein translation. These findings provide mechanistic insights into chronic ER stress in PBMCs and identify WNT5A and TNC as candidate biomarkers, pending further validation."

Journal • EIF2B4

Activated gasdermin E (GSDME) amplifies endoplasmic reticulum stress and inflammation in β-adrenoceptor overactivation-induced cardiac injury. (PubMed, Br J Pharmacol) - "GSDME functioned both downstream of cleaved caspase 3 to induce pyroptosis/inflammation and upstream of caspase3 to increase caspasen 3 cleavage by enhancing ER stress, suggesting that GSDME was a key molecule to amplify ER stress and inflammation and might play an essential role in the development of HF. GSDME represents a potential pharmacological target for HF."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation • CASP3 • GSDME

Activation of PPARγ Attenuates Age-Related Lacrimal Gland Dysfunction by Alleviating Endoplasmic Reticulum Stress-Mediated Ferroptosis. (PubMed, Invest Ophthalmol Vis Sci) - "The mice received an ERS inducer (tunicamycin), ERS inhibitor (4-phenylbutyric acid), a protein kinase R-like endoplasmic reticulum-resident kinase (PERK) inhibitor (GSK2606414), the ferroptosis inhibitors ferrostatin-1 (Fer-1), and deferoxamine mesylate (DFOM), or a peroxisome proliferator-activated receptor γ (PPARγ) agonist (rosiglitazone) or antagonist (GW9662). Our findings demonstrate that rosiglitazone alleviates age-related lacrimal dysfunction in mice through the PPARγ pathway. Our results offer a novel molecular target and therapeutic approach against age-related lacrimal gland disorders."

Journal • Fibrosis • Immunology • Metabolic Disorders • GPX4 • PPARG

Proteomic Analysis on Human Islets Suggests Nucleocytoplasmic Transport as a Mechanism of PERK Attenuation Effects in Diabetes. (PubMed, Mol Cell Proteomics) - "Proteomic analysis revealed that PERKi appears to modulate NCT of human islets under metabolic stress, thereby contributing to the restoration of β-cell function through regulation of relevant transcription factors. These findings suggested a novel mechanism of low-dose PERKi as a therapeutic approach of diabetes, in addition to the canonical unfolded protein response."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • KPNA4 • PDX1 • PERK

Overcoming ADC resistance in advanced colorectal cancer by dual targeting of TROP2 and PERK to suppress Wnt/β-catenin signaling. (PubMed, Cell Rep Med) - "Furthermore, combining IMMU132 with the PERK inhibitor GSK2606414 yields potent synergy across various CRC preclinical models. Mechanistically, this synergy stems from the enhanced suppression of ER stress and the oncogenic Wnt/β-catenin pathway. Thus, our findings reveal that co-targeting the DNA damage response, the PERK pathway, and the Wnt/β-catenin pathway is a promising strategy to overcome resistance to TROP2-directed antibody-drug conjugates (ADCs) in advanced CRC, providing a rational framework for combination therapies."

Journal • Colorectal Cancer • Oncology • Solid Tumor • ATF4 • TOP1

UFL1 deficiency impairs skeletal muscle development by activating PERK/eIF2α/ATF4/CHOP pathway-dependent apoptosis. (PubMed, Cell Signal) - "Notably, treatment with the PERK inhibitor GSK2606414 successfully reversed the UFL1 deficiency-induced upregulation of p-PERK, p-eIF2α, ATF4, and CHOP and rescued the apoptotic phenotype. Our study demonstrates for the first time that UFL1 is a critical regulator for maintaining myoblast survival and normal myofiber development, acting partly through suppressing the PERK-mediated ER sress. These findings provide novel insights into the pathogenesis of muscle developmental disorders and suggest UFL1 as a potential therapeutic target."

IO biomarker • Journal • B Cell Lymphoma • CNS Disorders • Developmental Disorders • Lymphoma • Oncology • Psychiatry • Targeted Protein Degradation • ATF4 • BAX • CASP3 • EIF2S1 • HSPA5 • PERK • TCF4

Trimethylamine N-oxide exacerbates myocardial ischemia-reperfusion injury by sustaining PERK/eIF2α activation and impairing ferredoxin reductase-dependent mitochondrial function. (PubMed, Transl Res) - "Pharmacological inhibition of PERK/eIF2α signaling (using GSK2606414 and ISRIB) reversed TMAO-induced ferredoxin reductase suppression, mitochondrial dysfunction, and MIRI exacerbation, indicating the key role of PERK/eIF2α signaling in this process...Through maintaining PERK/eIF2α activation, TMAO inhibits ferredoxin reductase expression thereby impairing ferredoxin reductase-dependent mitochondrial function. Pharmacological inhibition of the PERK/eIF2α pathway may represent a therapeutic strategy for alleviating MIRI with elevated TMAO."

Journal • Cardiovascular • Metabolic Disorders • Myocardial Infarction • Myocardial Ischemia • Reperfusion Injury • EIF2AK3

Mechanism of paraventricular nucleus H2S on PERK/TXNIP/NLRP3 pathway in male spontaneously hypertensive rats. (PubMed, Physiol Rep) - "This study aimed to investigate the regulatory effects of H2S on the PERK/TXNIP/NLRP3 pathway and the paraventricular nucleus (PVN) inflammatory responses by injecting S-adenosylmethionine (SAMe, an endogenous H2S agonist) or the PERK inhibitor GSK2606414 (GSK) into the PVN of spontaneously hypertensive rats (SHR). Additionally, we employed a lipopolysaccharide (LPS)-induced cell inflammation model and intervened with SAMe or the NLRP3 activator BMS-986299 (BMS) to further validate the relevant molecular mechanisms...This study found that H2S in the PVN improves spontaneous hypertension by inhibiting the PERK/TXNIP/NLRP3 pathway and reducing sympathetic activity. Cell experiments further confirmed that the inhibitory effect of H2S on this pathway is the key mechanism underlying its anti-inflammatory protective effects."

Journal • Preclinical • Cardiovascular • Hypertension • Inflammation • NLRP3 • TXNIP

MFN2-PERK Axis Regulates ER Stress in Parotid Glands of Aged Mice via MAMs. (PubMed, J Dent Res) - "Like 4-PBA, GSK2606414, a pharmacological antagonist of PERK, regulates ER stress and MAMs. Collectively, our data highlight disruption of the MFN2-PERK axis-mediated ER-mitochondrion connection as a cause of aging-induced parotid gland dysfunction."

Journal • Preclinical • MFN2

R-propranolol Promotes the Adipogenesis and Subsequent Apoptosis of Hemangioma Stem Cells through the PERK Signaling Pathway. (PubMed, Am J Pathol) - "This effect was attenuated by the PERK inhibitor GSK2606414. Immunostaining of clinical specimens further showed that PERK expression was higher in involuting IH samples than in proliferating IH samples. Together, these findings demonstrate that R-propranolol promotes adipogenesis and subsequent apoptosis of HemSCs through activation of the PERK signaling pathway."

Journal

Targeting gut-microbiota-dependent choline metabolite trimethylamine N-oxide ameliorates bone health in ovariectomized mice. (PubMed, Life Sci) - "These findings reveal a beneficial role of gut microbiota-dependent TMAO formation in mitigating estrogen-deficiency-induced bone loss and suggest that the TMAO-PERK signaling axis may provide new mechanistic insights and research directions for the prevention and intervention of postmenopausal osteoporosis."

Journal • Preclinical • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology

The PERK inhibitor GSK2606414 evokes developmental defects in zebrafish consistent with Wolcott-Rallison syndrome phenotypes. (PubMed, Pharmacol Rep) - No abstract available

Journal • CNS Disorders • Developmental Disorders • Metabolic Disorders • Psychiatry

Directional Modulation of the Integrated Stress Response in Neurodegeneration: A Systematic Review of eIF2B Activators, PERK-Pathway Agents, and ISR Prolongers. (PubMed, Biomedicines) - "Typical regimens included ISRIB 0.1-2.5 mg per kg given intraperitoneally (often two to three doses) with reduced ATF4 and phosphorylated eIF2α; oral GSK2606414 50 mg per kg twice daily for six to seven weeks, achieving brain-level exposures; continuous MK-28 delivery at approximately 1 mg per kg; and oral IFB-088 or Sephin1 given over several weeks. Directional ISR control yields consistent, context-dependent improvements in behavior, structure, or survival, with biomarker evidence of target engagement. Mechanism matching (down-tuning versus prolonging the ISR) and exposure-driven safety management are central for translation."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease • Movement Disorders • ATF4 • EIF2B4 • PPP1R15A

Integrated Stress Response (ISR) Modulators in Vascular Diseases. (PubMed, Cells) - "We further discuss pharmacological ISR modulators-including 2-aminopurine, C16, salubrinal, halofuginone, GSK2606414, and GSK2656157-which have demonstrated beneficial effects in preclinical models by suppressing inflammation, reducing apoptosis, and attenuating disease progression. Collectively, the ISR emerges as a critical regulatory node in vascular pathophysiology, and its selective, context-aware modulation represents a promising avenue for therapeutic intervention."

Journal • Review • Atherosclerosis • Cardiovascular • Hematological Disorders • Hypertension • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Thrombosis • ATF4

Baicalin Alleviates LPS-Induced Apoptosis of Periodontal Ligament Cells Via Inhibiting Endoplasmic Reticulum Stress. (PubMed, Int Dent J) - "BA shows therapeutic potential for periodontitis by inhibiting ER stress - mediated apoptosis and protecting periodontal tissue."

IO biomarker • Journal • Dental Disorders • Periodontitis • ATF4 • ATF6 • BAX • BCL2 • CASP3 • HSPA5

Endoplasmic Reticulum Stress Mediates Axon Initial Segment Shortening: Implications for Diabetic Brain Complications. (PubMed, J Mol Neurosci) - "Co-exposure to a PERK-specific inhibitor GSK2606414 prevented AIS shortening induced by tunicamycin. These results demonstrate ER stress is sufficient and necessary for AIS shortening in vitro. Our findings identify ER stress and AIS shortening as potential therapeutic targets in T2DM-related cognitive impairment."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

KLF10-IN-1 Attenuates RPE Cell Apoptosis and Experimental Diabetic Retinopathy Via the KLF10/PERK/eIF2α/ATF4/CHOP Pathway. (PubMed, Invest Ophthalmol Vis Sci) - "The PERK pathway was activated by CCT020312 and inhibited by GSK2606414 for rescue experiments...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."

Journal • Diabetes • Diabetic Retinopathy • Inflammation • Retinal Disorders • ATF4 • KLF10