salubrinal / Soochow University - LARVOL DELTA

4-Phenylbutyrate Plus Wildtype GAT-1 Augmentation: A Dual Therapy to Rescue SLC6A1 Variant-Associated Developmental and Epileptic Encephalopathy. (PubMed, Genes (Basel)) - "Variant effects were evaluated by (i) protein-structure prediction across nine stability-prediction algorithms using the cryo-EM-derived human GAT-1 template (PDB 7Y7W); (ii) 3H-GABA uptake assays in HEK293T cells and in human iPSC-derived astrocytes and cortical neurons; (iii) live-cell confocal microscopy of ER colocalization; (iv) pharmacologic rescue with PBA, TUDCA and salubrinal (v) and GAT-1 cDNA gene-augmentation, alone and in combination with PBA. GAT-1 p.Ala305Val is a trafficking-impaired, loss-of-function variant whose dysfunction is amenable to two convergent therapeutic axes: pharmacologic correction of folding and trafficking, and augmentation of functional transporter expression. These findings support a two-pronged precision-medicine framework for SLC6A1-related DEEs in which PBA increased the transporter function augmented by genetic approaches."

Journal • CNS Disorders • Epilepsy • Gene Therapies

Dexamethasone activates anti-tumor immunity in multiple myeloma by dismantling the GR-PPP1CB complex to restore STING/IRF3 signaling. (PubMed, J Immunother Cancer) - "This study uncovers a glucocorticoid-sensitive inhibitory axis wherein GR-PPP1CB constitutively suppresses STING-TBK1-IRF3 signaling in MM. DXM relieves this suppression, reactivating innate anti-tumor immunity. PP1 inhibition represents a promising therapeutic strategy to enhance anti-myeloma immunity and overcome immune evasion."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • CGAS • STING

4 Phenylbutyrate Plus Gene augmentation: A dual therapy To Rescue of SLC6A1 Variant Associated Developmental And Epileptic Encephalopathy. (PubMed, bioRxiv) - "Variant effects were evaluated by (i) protein-structure prediction across nine stability-prediction algorithms using the cryo-EM-derived human GAT-1 template (PDB 7Y7W); (ii) 3H-GABA uptake assays in HEK293T cells and in human iPSC-derived astrocytes and cortical neurons; (iii) live-cell confocal microscopy of ER colocalization; (iv) pharmacologic rescue with PBA, TUDCA and salubrinal (v) and GAT-1 cDNA gene-augmentation, alone and in combination with PBA. This work links the patient-derived SLC6A1 A305V variant to a defined molecular mechanism-GAT-1 destabilization, ER retention, and reduced GABA uptake-and demonstrates that the deficit is reversible by two independent interventions that converge at the same downstream endpoint of functional surface transporter. Because PBA is already clinically deployable and GAT-1 cDNA augmentation models a future viral or non-viral gene therapy, the combined-rescue logic provides a falsifiable path for precision medicine in..."

Journal • CNS Disorders • Epilepsy • Gene Therapies

A Macrophage/Monocyte-Related Four-Gene Signature for Prognostic Assessment of Uveal Melanoma: BTBD6, C2CD4B, CCL24, and S100A4. (PubMed, Hum Mutat) - "A significant negative correlation between RiskScore and the IC50 of XMD8-85, lapatinib, roscovitine, salubrinal, bexarotene, LFM-A13, FTI-277, and TGX221 chemotherapeutic agents was further noticed. In this study, we computationally identified genes associated with both disease progression and macrophage/monocyte-related characteristics in UVM and constructed a prognostic risk model with predicted immune infiltration patterns. These findings generate testable hypotheses that may inform future experimental studies on the immune mechanisms underlying UVM."

Biomarker • Gene Signature • Journal • Eye Cancer • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma • CD8 • S100A4

Construction of a ubiquitination-related gene prognostic model for breast cancer based on taxane treatment response (PubMed, Zhong Nan Da Xue Xue Bao Yi Xue Ban) - "The prognostic model based on E4F1, CBLL1, RNF13, and TRIM59 is an effective tool for predicting prognosis and drug sensitivity in breast cancer patients and may facilitate individualized treatment strategies. Among these, E4F1 may function as a potential oncogene and serve as a therapeutic target for enhancing taxane sensitivit."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • TRIM59

Mechanistic Study on MSC-EXO Loaded with Salubrinal for the Treatment of Osteomyelitis-Induced Bone Defects. (PubMed, FASEB J) - "In parallel, Sal-MSC-exo modulated autophagy-associated with increased p-eIF2α, eIF2α, LC3-I/II, and ALP and reduced p62-consistent with relief of maladaptive ER-stress-autophagy cross talk. Collectively, these findings indicate that Sal-MSC-exo mitigates osteomyelitis-associated bone loss and supports bone repair, highlighting its translational potential as a localized therapy for infection-induced bone defects."

Journal • Infectious Disease • Inflammation • Osteoporosis • Pain • ATF4

Salubrinal-activated integrated stress response protects against doxorubicin-induced cardiotoxicity via activating transcription factor 4-mediated antioxidant defense and glutathione homeostasis. (PubMed, Free Radic Biol Med) - "Our findings highlight the ISR as a vital survival mechanism in cardiomyocytes exposed to doxorubicin. Regulating antioxidant defenses through enhanced GSH homeostasis and ISR activation, particularly via pharmacological agents such as salubrinal, may offer a promising therapeutic strategy for mitigating doxorubicin-induced cardiotoxicity."

Journal • Cardiovascular • Metabolic Disorders • ATF4 • GDF15 • GPX4 • HSPA5 • TCF4

EIF2α-ATF4-CHAC1 Signalling Links ER Stress to Ferroptosis in Human Aortic Smooth Muscle Cells: Mechanistic Insights and Therapeutic Implications. (PubMed, J Cell Mol Med) - "Human aortic smooth muscle cells (HASMCs) and primary aortic smooth muscle cells (AoSMCs) were exposed to erastin (± ferrostatin-1), with pharmacologic modulation using buthionine sulfoximine (BSO; glutamate-cysteine ligase inhibitor) and salubrinal (selective EIF2α dephosphorylation inhibitor)...ER-stress signalling via PERK-EIF2α-ATF4-CHAC1 constitutes a proximal driver of ferroptosis in human aortic SMCs by eroding glutathione tone and disabling GPX4, thereby promoting lipid peroxidation in an iron-rich milieu. Pharmacologic tuning of EIF2α phosphorylation and glutathione biosynthesis modulates ferroptotic susceptibility, nominating EIF2α-ATF4-CHAC1, GPX4/GSH homeostasis and iron handling as actionable nodes to preserve VSMC integrity in oxidizing vascular environments."

Journal • ACSL4 • ALOX15 • ATF4 • CHAC1 • GPX4 • HSPA5

Stress-adapted Immunity: The Integrated Stress Response as a Driver of S. aureus Biofilm Persistence (IMMUNOLOGY 2026) - "These findings identify the ISR as a pivotal regulator of immune dynamics and biofilm persistence. Understanding how stress-adaptive pathways shape leukocyte function may reveal novel immunomodulatory strategies to overcome treatment-refractory biofilm infections."

Brain Cancer • CNS Disorders • Epilepsy • Infectious Disease • Solid Tumor • ATF4

NUFIP1-engineered exosomes modulate propofol-induced neurotoxicity in neonatal rats via the ERS apoptotic pathway. (PubMed, Apoptosis) - "Importantly, we directly validated key ERS/apoptosis markers and functionally confirmed the pathway's role through pharmacological rescue experiments with Salubrinal. In conclusion, NUFIP1-engineered exosomes regulate propofol-induced nerve injury through the ERS apoptotic pathway, offering novel mechanistic insights with potential implications for addressing pediatric neurodevelopmental impairments."

Journal • Preclinical • Anesthesia • CNS Disorders • Cognitive Disorders • Mental Retardation • Pediatrics

PP1 phosphatase complex at the hub of the integrated stress response: A potential therapeutic target in multiple myeloma (AACR 2024) - "Immunoblot analysis showed activation of ER stress pro-apoptotic executors PUMA, NOXA, and cleavage of caspase-12 in PPP1R15B knockdown cells.Furthermore, we examined the therapeutic effects of eIF2α dephosphorylation inhibitors, Salubrinal and Raphin1, on MM cells...Similar changes in the expression patterns of ISR-related genes were observed in response to eIF2α dephosphorylation inhibitors. Taken together, our study suggests that targeting PPP1R15B-PP1c complex or maintaining eIF2α hyperphosphorylation may serve as a new therapeutic approach in MM, which warrants further investigation."

Hematological Malignancies • Multiple Myeloma • Oncology • CASP12 • PPP1R15A • PPP1R15B • SDC1 • TNS1

PHARMACOLOGICAL MODULATION OF PROTEOSTASIS AS A STRATEGY TO BOOST THYMIC REGENERATION AND T CELL IMMUNITY (EBMT 2026) - "Among the hits, the antiparasitic drug nitazoxanide (NTZ) induced proteasome inhibition and Foxn1 expression without cytotoxicity, unlike other proteasome inhibitors...Consistently, pharmacological activation of UPR with salubrinal increased Foxn1 and Atf4 expression, and several other hits from our screen were known ER stress inducers, supporting the notion that Foxn1 induction reflects a broader stress-related mechanism linked to alterations in cellular proteostasis... Our findings uncover proteotoxic stress as a novel mechanism regulating Foxn1 expression and position NTZ as a promising thymic regenerative therapy that accelerates recovery without disrupting physiological T-cell selection or tolerance. Evaluation of T-cell recovery in clinically relevant HSCT mouse models is ongoing, supporting the translational potential of our study for allo-HCT recipients and individuals with thymic insufficiency due to aging, infections, or anti-neoplastic therapies."

IO biomarker • Bone Marrow Transplantation • Graft versus Host Disease • Immunology • Infectious Disease • ATF4 • CD24 • CD5 • CD69 • CD8 • FOXP3 • IL2RA • TRB • XBP1

Tetramethylpyrazine mitigates ER-stress-driven ATF4/CHOP apoptosis to protect dopaminergic neurons in cellular and MPTP models of Parkinson's disease. (PubMed, Neuropharmacology) - "Crucially, these therapeutic benefits were largely negated by co-administering Salubrinal (SAL), an inhibitor of eukaryotic initiation factor 2 alpha (eIF2α) dephosphorylation known to sustain ATF4 activation. These findings support a model where TMP's neuroprotective action is associated with the inhibition of the ERS-induced ATF4/CHOP apoptotic axis, highlighting this pathway as a promising therapeutic target for PD."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • ATF3 • ATF4 • TCF4

Single-cell and transcriptomic profiling reveal stemness-driven immune evasion in obstructive sleep apnea (OSA) associated lung cancer. (PubMed, J Cancer) - "Drug sensitivity analyses further suggested that stemness-high tumors may exhibit increased susceptibility to selected kinase inhibitors (Dasatinib, A-770041) and metabolic modulators (Phenformin, Salubrinal). OSA-associated IH is linked to stemness-associated transcriptional plasticity, immune suppression, and adverse clinical outcomes in lung cancer. The identified stemness-based gene signature provides a robust prognostic biomarker and highlights potential therapeutic vulnerabilities, supporting integrative strategies that combine stemness and immune -targeted approaches with immunotherapy in OSA-associated lung cancer."

IO biomarker • Journal • Lung Cancer • Obstructive Sleep Apnea • Oncology • Respiratory Diseases • Sleep Disorder • Solid Tumor • LAG3 • MELTF • MELTF • PD-1 • PD-L1

Novel mtDNA methylation-associated prognostic signatures in colorectal cancer. (PubMed, Front Oncol) - "Sorafenib, Salubrinal, and Roscovitine were positively correlated with the risk score, whereas WO2009093972 was negatively correlated. Additionally, this study identified several target genes such as FBXO25 with TINAG, CCDC28A with EPHB2, and SH2D6 with FCN3, with subsequent validation achieved through qPCR and western blotting. In conclusion, this study identifies three prognostic genes, providing new insights into CRC pathogenesis and potential therapeutic strategies."

Journal • Colorectal Cancer • Oncology • Solid Tumor • EPHB2

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

Functional interplay between endoplasmic reticulum stress and mitochondrial activity in a post-ovulatory aging model of mouse oocytes. (PubMed, J Assist Reprod Genet) - "In this POA model, ER-mitochondria coupling detected in freshly ovulated oocytes appeared attenuated. While our single-marker readouts (GRP78 and MitoSOX) are limited proxies, independent targeting of either organelle modestly improved blastocyst formation. These data support a hypothesis-generating framework for future studies in maternal aging models. Results were obtained under 20% O₂ culture and may be conservative relative to physiologic (5%) O₂ conditions."

Journal • Preclinical • Metabolic Disorders • HSPA5

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