STF-083010 / Shanghai Jiao Tong University - LARVOL DELTA

Identification and Sorting of Adipose Inflammatory and Metabolically Activated Macrophages in Diet-Induced Obesity. (PubMed, Bio Protoc) - "• Facilitates downstream gene expression profiling from sorted ATM subsets. • Validated using a metabolic intervention (IRE1 RNase inhibitor STF-083010) in a mouse obesity model."

Journal • Genetic Disorders • Inflammation • Metabolic Disorders • Obesity • CD9 • ERN1 • ITGAX

Ire1 inhibitors attenuate Candida albicans pathogenicity and demonstrate potential for application in antifungal therapy. (PubMed, Front Microbiol) - "Three candidate inhibitors-MKC8866, STF083010, and 4μ8c-were predicted to interact with Ire1, but only 4μ8c exhibited consistent inhibitory activity. These findings demonstrate that pharmacological targeting of the UPR pathway through Ire1 inhibition is feasible. 4μ8c emerges as a promising candidate that diminishes the adaptability and pathogenicity of Candida albicans, offering new insights into antifungal therapeutic development."

Journal • Infectious Disease • ERN1

IRE1α modulates M1 oncolytic virus sensitivity via ER stress regulation in bladder cancer. (PubMed, Cancer Drug Resist) - "In vivo, M1 plus STF083010 achieved greater tumor suppression than monotherapy without added toxicity...Inhibiting IRE1α enhances ER stress and potentiates the oncolytic effect of M1 virus. Targeting IRE1α may improve M1-based virotherapy outcomes in accessible tumors."

IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

Cadmium induces autophagy via IRE1 signaling pathway activated by Ca2+ in GC-2spd cells. (PubMed, Reprod Toxicol) - "Conversely, the addition of 2-APB and STF-083010 reversed these effects, synergistically restoring intracellular Ca2+ homeostasis and inhibiting ERS to promote cell health. This study provides a new therapeutic strategy for Cd-induced male reproductive disorders."

Journal • BECN1 • ERN1

IRE1α/TRAF2/NF-κB pathway promotes apoptosis via regulating inflammatory cytokines and aggravates brain injury after SAH. (PubMed, J Stroke Cerebrovasc Dis) - "The IRE1α/TRAF2/NF-κB signal pathway was activated and promoted apoptosis by promoting the expression of inflammatory cytokines after SAH."

Journal • CNS Disorders • Hematological Disorders • Subarachnoid Hemorrhage • Vascular Neurology • CASP3 • HSPA5 • IL1B • IL6 • TNFA

The transcription factor XBP1 regulates mitochondrial remodel and autophagy in spontaneous abortion. (PubMed, Int Immunopharmacol) - "XBP1s inhibition restored mitochondrial homeostasis and promoted autophagy by modulating the TRAF6/mTORC2 axis under ERS conditions, providing novel mechanistic insights into SA pathogenesis and potential therapeutic targets."

Journal • Metabolic Disorders • Oncology • Targeted Protein Degradation • IL18 • IL1B • IL6 • TNFA • TRAF6 • XBP1

The Protective Role of the IRE1α/XBP1 Signaling Cascade in Autophagy During Ischemic Stress and Acute Kidney Injury. (PubMed, Cell Stress Chaperones) - "Additionally, the impacts of IRE1α overexpression and pharmacological agents, IXA6 (IRE1α agonist) and STF083010 (IRE1α inhibitor), were evaluated on autophagy regulation...The IRE1α/XBP1 pathway is a critical regulator of autophagy in renal TECs during ischemic stress, suggesting that pharmacological modulation of this pathway may offer therapeutic avenues for preventing or mitigating AKI. Enhanced understanding of these mechanisms may lead to novel strategies for kidney disease management."

Journal • Acute Kidney Injury • Cardiovascular • Chronic Kidney Disease • Nephrology • Renal Disease • Reperfusion Injury • BECN1 • HSPA5 • XBP1

Chlorpyrifos-oxon induced neuronal cell death via endoplasmic reticulum stress-triggered apoptosis pathways. (PubMed, Toxicol In Vitro) - "Pretreatment with STF-083010 (an IRE1α inhibitor) partially attenuated CPO-induced apoptosis...Collectively, our results indicate that CPO exposure exerts neuronal cytotoxicity via ER stress downstream-regulated IRE1α/XBP1 signaling pathway and ROS generation-triggered apoptosis. These findings highlight the role of ER stress in CPF-induced neurotoxicity, and provide a promising target for the intervention of organophosphate-associated neurodegenerative diseases."

Journal • CNS Disorders • HSPA5 • XBP1

Astragaloside IV Alleviates Podocyte Injury in Diabetic Nephropathy through Regulating IRE-1α/NF-κ B/NLRP3 Pathway. (PubMed, Chin J Integr Med) - "AS-IV could reduce ERS and inflammation, improve podocyte pyroptosis, thus exerting a podocyte-protective effect in DN, through regulating IRE-1α/NF-κ B/NLRP3 signaling pathway."

Journal • Diabetes • Diabetic Nephropathy • Inflammation • Nephrology • Renal Disease • ERN1 • HSPA5 • IL1B • NLRP3 • NPHS1

The total xanthones extracted from Gentianella acuta alleviates HFpEF by activating the IRE1α/Xbp1s pathway. (PubMed, J Cell Mol Med) - "Mechanistic investigations revealed that TXG could activate the inositol-requiring enzyme 1α (IRE1α)/X-box-binding protein 1 (Xbp1s) signalling pathway, but the knockdown of IRE1α using the IRE1α inhibitor STF083010 or siRNA-IRE1α impaired the ability of TXG to ameliorate cardiac remodelling in HFpEF models. In conclusion, TXG alleviates myocardial hypertrophy, fibrosis and apoptosis through the activation of the IRE1α/Xbp1s signalling pathway, suggesting its potential beneficial effects on HFpEF patients."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • ERN1 • XBP1

Bax Inhibitor-1 preserves pancreatic β-cell proteostasis by limiting proinsulin misfolding and programmed cell death. (PubMed, Cell Death Dis) - "Pharmaceutical IRE1α inhibition with STF-083010 reversed β-cell failure and normalized the metabolic phenotype. These results uncover a new protective role for BI-1 in pancreatic β-cell physiology as a stress integrator to modulate the UPR triggered by accumulating unfolded proinsulin in the ER, as well as autophagy and programmed cell death, with consequences on β-cell function and insulin secretion. In pancreatic β-cells, BI-1-/- deficiency perturbs proteostasis with proinsulin misfolding, ER stress, terminal UPR with overwhelmed IRE1α/XBP1s/CHOP activation, inflammation, β-cell programmed cell death, and diabetes."

Journal • Diabetes • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Inflammation • Metabolic Disorders • Obesity • CASP1 • ERN1 • IL1B • NLRP3

Peste des petits ruminants virus infection induces endoplasmic reticulum stress and apoptosis via IRE1-XBP1 and IRE1-JNK signaling pathways. (PubMed, J Vet Sci) - "PPRV infection induces ER stress and IRE1 activation, resulting in apoptosis and enhancement of virus replication through IRE1-XBP1s and IRE1-JNK pathways."

IO biomarker • Journal • Infectious Disease • BAX • BCL2 • CASP3 • CASP9 • ER • ERN1 • HSPA5 • XBP1

IRE1α/XBP-1 promotes β-catenin signaling activation of airway epithelium in lipopolysaccharide-induced acute lung injury. (PubMed, Pulm Pharmacol Ther) - "These results illustrated that IRE1α/XBP1 pathway promoted the activation of airway epithelial β-catenin signaling in LPS-induced ALI."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Inflammation • Pulmonary Disease • Respiratory Diseases • ERN1 • HSPA5 • XBP1

N-methyl-d-aspartate receptor 1 activation mediates cadmium-induced epithelial-mesenchymal transition in proximal tubular cells. (PubMed, Sci Total Environ) - "Inhibition of NMDAR1 by pharmacological antagonist MK-801 significantly attenuated Cd-induced Ca influx, ER stress, and EMT. Pretreatment with the IRE-1α/XBP-1s pathway inhibitor STF-083010 also restored the epithelial phenotype of Cd-treated HK-2 cells. Therefore, our findings suggest that NMDAR1 activation mediates Cd-induced EMT in proximal epithelial cells likely through the IRE-1α/XBP-1s pathway, supporting the idea that NMDAR1 could be a potential therapeutic target for Cd-induced renal damage."

Journal • ERN1 • XBP1

Emodin, an Emerging Mycotoxin, Induces Endoplasmic Reticulum Stress-Related Hepatotoxicity through IRE1α-XBP1 Axis in HepG2 Cells. (PubMed, Toxins (Basel)) - "To test this hypothesis, a novel IRE1α inhibitor, STF-083010, was used...Furthermore, the apoptosis rate was increased in a dose-dependent manner with emodin treatment. Thus, emodin induced ER stress in HepG2 cells by activating the IRE1α-XBP1 axis and induced apoptosis, indicating that emodin can cause hepatotoxicity."

IO biomarker • Journal • Hepatology • Lymphoma • Oncology • BAX • BCL2 • CASP3 • ER • ERN1 • HSPA5 • XBP1

STF-083010 an inhibitor of IRE1α endonuclease activity affects mitochondrial respiration and generation of mitochondrial membrane potential. (PubMed, Toxicol In Vitro) - "Our results indicate that STF-083010 has important impact on mitochondrial functions independently of its ability to inhibit endonuclease activity of IRE1α that is involved in activation of IRE1α-XBP1 axis of the unfolded protein response after ER stress. The impact of STF-083010 on mitochondrial functions could be associated with its possible off-target effect."

Journal • Hepatology • Liver Failure • Oncology • ERN1 • XBP1

TSG-6 alleviates cerebral ischemia/reperfusion injury and blood-brain barrier disruption by suppressing ER stress-mediated inflammation. (PubMed, Brain Res) - "The further use of specific inhibitors of ER stress, 4-phenyl butyric acid (4-PBA), PERK (GSK2656157), and IRE1α (STF083010) demonstrated the ability of ER stress to drive inflammatory activity in the context of CIR injury i the PERK-eIF2α-NF-κB and IRE1α-TRAF2-NF-κB pathways. Consistently, the activation of ER stress using tunicamycin resulted in reversing the beneficial effects of TSG-6 on CIR-associated BBB disruption and neurological damage in vitro and in vivo. Treatment with TSG-6 can protect against CIR injury via the inhibition of ER stress-related inflammatory activity induced through the PERK-eIF2α-NF-κB and IRE1α-TRAF2-NF-κB pathways."

Journal • Cardiovascular • Inflammation • Oncology • Reperfusion Injury • IL1B • IL6 • NF-κβ • TNFA

DHA induces adipocyte lipolysis through endoplasmic reticulum stress and the cAMP/PKA signaling pathway in grass carp (Ctenopharyngodon idella). (PubMed, Anim Nutr) - "Additionally, STF-083010, a specific inositol-requiring enzyme 1α (IRE1α)-inhibitor, attenuated the effects of DHA on lipolysis, demonstrating that IRE1α and X-box binding protein 1 potentially participate in DHA-induced lipolysis...The present study elucidated the molecular mechanism for DHA-induced lipolysis in grass carp adipocytes and emphasized the importance of ER stress and the cAMP/PKA pathway in DHA-induced lipolysis. These results deepen our understanding of ameliorating lipids deposition in freshwater fish by targeting DHA."

Journal • Metabolic Disorders • ERN1 • XBP1

Deubiquitylase OTUD3 Mediates Endoplasmic Reticulum Stress through Regulating Fortilin Stability to Restrain Dopaminergic Neurons Apoptosis. (PubMed, Antioxidants (Basel)) - "The ratio of p-IRE1α/IRE1α, and the expression of X-box binding protein 1-spliced (XBP1s) were remarkably increased after OTUD3 knockdown, which was inhibited by IRE1α inhibitor STF-083010 treatment...Taken together, we revealed that OTUD3 knockout-induced injury of dopaminergic neurons might be caused by activating IRE1α signaling in ER stress. These findings demonstrated that OTUD3 played a critical role in dopaminergic neuron neurodegeneration, which provided new evidence for the multiple and tissue-dependent functions of OTUD3."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • Targeted Protein Degradation • ERN1 • XBP1

XBP1s acts as a transcription factor of IRE1α and promotes proliferation of colon cancer cells. (PubMed, Arch Biochem Biophys) - "Overexpression of XBP1s also activated the regulated IRE1-dependent decay of mRNAs, which was suppressed by IRE1α RNase inhibitor STF083010...The results suggest that XBP1s functions to induce IRE1α expression and promote cancer cell proliferation. Our findings reveal a previously unknown mechanism of IRE1α expression by XBP1s and highlight the role of this regulation in proliferation of colon cancer cells, suggesting that IRE1α-targeting is a potential therapeutic strategy for colon cancer."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ERN1 • XBP1

Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca axis. (PubMed, J Neuroinflammation) - "In SAE, Erbin inhibits IRE1/Xbp1s pathway activity and reduces the ER Ca influx to the cytoplasm, reducing microglial pyroptosis."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Immunology • Infectious Disease • Inflammation • Septic Shock • ERN1

TSG-6 inhibits hypertrophic scar fibroblast proliferation by regulating IRE1α/TRAF2/NF-κB signalling. (PubMed, Int Wound J) - "Overall, ER stress was found to trigger inflammatory activity in HSFs via the IRE1α-TRAF2 axis, as confirmed with the specific inhibitor of IRE1α STF083010. Additionally, the effects of TSG-6 on apoptosis, collagen I, collagen III, α-SMA, and PCNA of HSFs were reversed by the IRE1α activator thapsigargin (TG). These data suggest that TSG-6 administration can effectively suppress the proliferation of HSFs in part via the inhibition of IRE1α-mediated ER stress-induced inflammation (IRE1α/TRAF2/NF-κB signalling)."

Journal • Immunology • Inflammation • Oncology • ERN1 • IL1B • IL6 • PCNA • TNFA

Targeting autophagy increases the efficacy of proteasome inhibitor treatment in multiple myeloma by induction of apoptosis and activation of JNK. (PubMed, BMC Cancer) - "In this study we showed that combined inhibition of autophagy and the proteasome synergistically induces cell death in multiple myeloma. Hence, we consider the implication of pharmaceutical inhibition of autophagy together with proteasome inhibition and UPR-directed therapy as promising novel in vitro treatment strategy against multiple myeloma."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • MAPK8 • XBP1

ER Stress is Involved in Mast Cells Degranulation via IRE1α/miR-125/Lyn Pathway in an Experimental Intracerebral Hemorrhage Mouse Model. (PubMed, Neurochem Res) - "STF083010, an inhibitor of IRE1α, was administered intranasally at 1 h after ICH induction...The downregulation of Lyn kinase, tryptase, IL-17A, TNF-α, and decreased mast cells number were reversed by antimiR-125. The present findings demonstrate that IRE1α inhibition attenuates mast cells degranulation and neuroinflammation, at least partially, through IRE1α/miR-125/Lyn signaling pathway after ICH."

Journal • Preclinical • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Immunology • Inflammation • Oncology • IL17A • LYN • MIR125 • miR-125b • TNFA • XBP1

Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy. (PubMed, Cell Death Dis) - "Acetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes...Pharmacological inhibition of XBP1 using pre-treatment with STF-083010 [STF, 75 mg/kg] and autophagy induction with Rapamycin [RAPA, 8 mg/kg] or blockade with Chloroquine [CQ, 60 mg/kg] was also undertaken in vivo...Genetic and pharmacological inhibition of Xbp1 specifically in hepatocytes ameliorated APAP-induced liver injury by enhancing autophagy and decreasing CYP2E1 expression. These findings provide the basis for the therapeutic restoration of ER stress and/or induction of autophagy in patients with hyperacute liver injury."

Journal • Hepatology • Liver Failure • CYP2E1 • MAPK8 • XBP1