thapsigargin / University of Nottingham, Pirbright Institute - LARVOL DELTA

CLPTM1L: A candidate therapeutic target in multiple myeloma (ASH 2025) - "siRNA was used to knock down CLPTM1L in OPM2 and RPMI8226 myeloma, followed by measurement of cell growth and survival, immunoblot analysis of AKT activation and regulators of programmed cell death, and determination of sensitivity (IC 50 ) to bortezomib...Treatment of OPM2 using the ER stress inducer, thapsigargin, led to upregulation of CLPTM1L together with increased levels of the ER stress markers, calnexin and CHOP... CLPTM1L is an ER stress-inducible candidate myeloma gene that regulates cell growth / survival through AKT signaling. Its inhibition sensitizes myeloma cells to proteasome inhibitors. Ongoing studies in our group are aimed at elucidating this mechanism in greater depth."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • BCL2 • BCL2L1 • CASP3 • CLPTM1L • HSPA5

Regional Differences in Calcium Dynamics in the Intact Lens: The Role of TRPV Channels in Lens Calcium Regulation. (PubMed, Invest Ophthalmol Vis Sci) - "Central and equatorial epithelial cells exhibited biphasic Ca²⁺ responses to thapsigargin, consistent with ER-dependent release and store-operated Ca²⁺ entry, whereas differentiating fiber cells lacked detectable ER-dependent Ca²⁺ mobilization...This study establishes a confocal imaging approach for simultaneous analysis of Ca²⁺ dynamics in epithelial and fiber cells of the intact lens. Our findings reveal region-specific differences in Ca²⁺ regulation and provide insight into how TRPV1 and TRPV4 activate signaling pathways that regulate lens ion homeostasis and water transport to maintain optical properties."

Journal

Cell-cell fusion limits activation of the unfolded protein response induced by the Nipah virus glycoproteins. (PubMed, J Virol) - "Here, we show that irreversible ER stress induced by thapsigargin resulted in broad expression of UPR target genes and potently inhibited NiV infection...However, this activation is limited by the cell-cell fusion mediated by the glycoproteins, probably due to dilution effects. This study is the first to investigate the interplay between NiV and UPR activation and proposes a novel strategy by which fusogenic viruses may limit the ER stress responses triggered by their glycoproteins."

Journal • Infectious Disease • ERN1 • XBP1

Development and validation of a novel disulfidptosis-related gene signature for prediction of survival and immune microenvironment in osteosarcoma by WGCNA analysis. (PubMed, Discov Oncol) - "Besides, patients in the high-risk group exhibited lower IC50 values for vorinostat, elesclomol, OSI-906, pyrimethamine, thapsigargin, and doxorubicin, but a higher IC50 value for cisplatin, compared to those in the low-risk group, indicating differential drug sensitivities. In summary, we established a robust DRGs signature comprising BTN3A1, CEBPA, KCNAB2, TBX21, and MYC, which showed strong prognostic value and predictive potential for immune status and drug sensitivity in OS. Notably, functional experiments confirmed that BTN3A1 acted as a tumor suppressor in OS, highlighting it as a promising therapeutic target."

Gene Signature • IO biomarker • Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • BTLA • BTN3A1 • CEBPA • LAG3 • PD-L1 • PD-L2 • TBX21

Role of the Ca2+-ATPase Pump (SERCA) in Capacitation and the Acrosome Reaction of Cryopreserved Bull Spermatozoa. (PubMed, Cells) - "All changes occurred in concordance with a significant increase in intracellular calcium concentration (Ca2+). Our findings suggest that a thapsigargin-sensitive Ca2+ pump consistent with SERCA activity remains responsive in cryopreserved spermatozoa from the bull studied, under specific cryopreservation and incubation conditions tested, and may contribute to Ca2+ handling, motility changes, and premature acrosomal exocytosis."

Journal

Implementing N-terminomics and machine learning to probe Nt-arginylation. (PubMed, Nat Commun) - "By applying the prediction models with an additional statistical filter, we identify 134 Nt-arginylation sites in thapsigargin-treated HeLa cells...Temporal profiling reveals that ATF4 increases early post-stress, followed by arginylation at caspase-3 substrates and ER signal-cleaved proteins. Our approach enables sensitive detection of rare N-terminal modifications, offering potential for biomarker and drug target discovery."

Journal • ATF4 • CASP3

Vasodilatory effects of trans-3-methoxy-β-nitrostyrene, a synthetic nitroderivative, on rat thoracic aorta: involvement of soluble guanylate cyclase stimulation. (PubMed, J Cardiovasc Pharmacol) - "T3MN-induced vasodilatory effects remained unaffected by indomethacin, MDL-12,330A or glybenclamide but were significantly reduced by endothelium removal, L-NAME, ODQ, LY294002, TEA, 4-AP, and apamin. Under Ca2+-free conditions, T3MN was unresponsive to transient contractions evoked by caffeine, whereas it inhibited contractions induced by (i) the protein kinase C activator phorbol 12-myristate 13-acetate, (ii) the tyrosine phosphatase inhibitor sodium orthovanadate, (iii) exogenous calcium influx via receptor- or voltage-operated Ca2+ channels and (iv), in an ODQ-preventable manner, those evoked by PHE or Ca2+ influx through stores-operated Ca2+ channels activated by thapsigargin-induced Ca2+ store depletion. In conclusion, T3MN induced a potent vasorelaxant effect that seems to be mediated partly by an endothelium-dependent mechanism involving activation of the Akt/eNOS/NO pathway and partly by an endothelium-independent mechanism through activation of the sGC/cGMP/PKG..."

Journal • Preclinical • NOS3

T-prolymphocytic leukemia(T-PLL) – What are recent improvements? (DGHO 2025) - "With the aim to further improve clinical outcomes, a prospective phase-II trial was conducted by the German CLL Study group using an induction therapy with fludarabine, cyclophosphamide and mitoxantrone (FMC) followed by alemtuzumab consolidation therapy...CIBMTR Data of 266 patients with T-PLL demonstrated a 4-year disease-free survival (DFS) of 25.7% and OS of 30.0%.There are recent clinical pilot data derived from drug screening efforts that provide valuable insights: venetoclax, HDAC-inhibition plus idasanutlin (MDM2 antagonist, activation of p53), and drugs targeting autophagy (thapsigargin and bafilomycin A1), nuclear export (selinexor) or inhibitor of apoptosis proteins (IAPs; birinapant). Valuable trial data teach us on the limited applicability of pre-clinical results, i.e. the limited efficacy of venetoclax+ibrutinib or of itacitinib + alemtuzumab.Overall, responses after induction therapy remain dissatisfactory as most patients relapse even after a CR..."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Prolymphocytic Leukemia

Dual Targeting of KDM1A/LSD1 and Endoplasmic Reticulum Stress Pathways as a Therapeutic Strategy in Glioblastoma (SNO 2025) - " The combinatorial effects of KDM1A knockdown or pharmacological inhibition with NCD38, together with ER stress inducers thapsigargin and brefeldin A, were assessed using cell viability, neurosphere formation, extreme limiting dilution, and apoptosis assays... Our findings demonstrate that KDM1A inhibition induces ER stress in GSCs and targeting KDM1A in combination with ER stress induction represents a promising therapeutic strategy for glioblastoma."

Brain Cancer • Glioblastoma • Solid Tumor • KDM1A

New Role of Protein Misfolding Corrector in the ER Stress-Inflammation Axis: Possible Therapeutic Indication in Neuronal and Epithelial Tumor Cells. (PubMed, Int J Mol Sci) - "In this study, the efficacy of the drug Vx-445 (Elexacaftor), used in the pharmacological treatment of cystic fibrosis, was assessed in human adenocarcinomic basal alveolar epithelial (A549) and neuronal (SH-SY5Y) cell lines, where ER stress was induced by Thapsigargin. The results obtained suggest a significant effect of Vx-445 in restoring cellular homeostasis, leading to reduced expression of inflammation-related proteins, such as IL-6, tested by ELISA. Although preliminary, these results encourage further studies to explore the potential repurpose of Vx-445 as a therapeutic candidate for conditions involving ER stress and chronic inflammatory diseases associated with protein misfolding, beyond its current use in cystic fibrosis."

Journal • Alzheimer's Disease • CNS Disorders • Cystic Fibrosis • Genetic Disorders • Huntington's Disease • Immunology • Inflammation • Movement Disorders • Oncology • Parkinson's Disease • Proteinopathy • Pulmonary Disease • Respiratory Diseases • Solid Tumor • CASP4 • IL6 • STAT3

The Mechanism of LTXN4C-Induced Ca2+ Influx Involves Latrophilin-Mediated Activation of Cav2.x Channels. (PubMed, Int J Mol Sci) - "LPHN1 stimulation by LTXN4C induced a small Ca2+ release sensitive to thapsigargin, and a strong, gradual influx of Ca2+, which was insensitive to thapsigargin...These channels mediate an initial Ca2+ influx that triggers Ca2+-induced Ca2+ release and SOCE. This mechanism, elucidated in model cells, can explain how LTXN4C stimulates neurotransmitter release."

Journal • Neuroblastoma • Oncology • Solid Tumor • CAV2

Fine-Tuning of the Endoplasmic Reticulum Stress Response Mechanism Plays a Key Role in Cellular Survival-A Mathematical Study. (PubMed, Int J Mol Sci) - "There are a variety of well-established stressors on the market that can be used to induce ER stress under laboratory conditions (i.e., thapsigargin and tunicamycin)...By using various mathematical methods, our systems biology approach presented here seeks to answer how the well-known ER stressors affect the dynamic characteristic of the control network, specifically highlighting how we can delay the negative impact of ER stress. Furthermore, using mathematical models, we make suggestions on which ER stressors may be useful in which therapeutic treatment."

Journal • Diabetes • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Metabolic Disorders

Thapsigargin suppresses porcine hemagglutinating encephalomyelitis virus replication by disrupting host energy metabolism. (PubMed, Virol Sin) - "Furthermore, metabolic reprogramming is associated with the antiviral effect of Tg and is required for productive PHEV infection. Overall, our findings highlight that Tg plays a crucial role in combating viral infections by targeting host energy metabolism shared by pathogenic microorganisms, suggesting that targeting key nodes of host metabolic processes may be a strategy for designing antiviral drugs against coronaviruses."

Journal • Preclinical • CNS Disorders • Infectious Disease • Novel Coronavirus Disease

Dual Targeting of KDM1A/LSD1 and Endoplasmic Reticulum Stress Pathways as a Therapeutic Strategy in Glioblastoma (WFNOS 2025) - " The combinatorial effects of KDM1A knockdown or pharmacological inhibition with NCD38, together with ER stress inducers thapsigargin and brefeldin A, were assessed using cell viability, neurosphere formation, extreme limiting dilution, and apoptosis assays... Our findings demonstrate that KDM1A inhibition induces ER stress in GSCs and targeting KDM1A in combination with ER stress induction represents a promising therapeutic strategy for glioblastoma."

Brain Cancer • Glioblastoma • Solid Tumor • KDM1A

Adenylosuccinate lyase (ADSL) is a pan-cancer prognostic and immune biomarker with distinct roles in hepatocellular carcinoma. (PubMed, Discov Oncol) - "ADSL holds potential as a promising prognostic marker for OS in various cancer types, particularly in HCC. Additional research is needed to confirm these findings and to understand how ADSL affects cancer development."

Biomarker • Journal • Pan tumor • Hepatocellular Cancer • Oncology • Solid Tumor

Hypoxic regulation of insulin receptor substrate 2 gene expression is differently regulated by endoplasmic reticulum stress and hydrocortisone in normal human astrocytes and glioblastoma cells. (PubMed, Endocr Regul) - "Tunicamycin and thapsigargin were used for the induction of ER stress. Conclusion. Our findings provide evidence that hypoxic regulation of IRS2 gene expression is modified by inducers of ER stress and hydrocortisone, but differently in normal astrocytes and glioblastoma cells and that the combined effect of hypoxia with ER stress and hydrocortisone greatly enhanced this gene expression in both cell types, especially in the glioblastoma cells."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • HIF1A • IGF1 • IRS2

Inhibiting FOXM1 Sensitizes Myeloma Cells to BCL2 Inhibitor Venetoclax By Repressing MYC Pathway (ASH 2023) - "We identified Dasatinib and Panobinostat that killed FOXM1KO OPM2 cells much more than FOXM1WT cells...Thirdly, CMap, a large-scale compendium of functional perturbations in cultured human cells coupled to a gene expression read-out, implicated a synergy between NB73 and Thapsigargin that was verified by ZIP drug synergy scoring assay... We identified FOXM1-targeted therapies consisting of novel FOXM1 inhibitor NB73 and FDA-approved drugs in vitro. We are addressing how the combo represses MYC pathway to sensitize MM cells to BCL2 inhibitor Venetoclax."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CCNA2 • CDC20 • FOXM1 • IFNA1 • PLK1

Broad phenotypic pathway discovery in motor neurons for motor neuron diseases (MND) therapeutic development (ALS-MND 2025) - " Through use of an acute stress assay with thapsigargin, we demonstrate a decreased capacity of mutant cells to enact a stress response when compared against an isogenic control (1.3–2.5 fold lower increase in G3BP1+ TDP43+ granules, p < 0.05)... Acute stress provides a robust phenotype in motor neurons across multiple models and differentiation techniques, however effect size remains inadequate for typical drug discovery assays. Upstream unbiased assessment of multiple pathways becomes possible via omics assessment, providing novel assays with greater windows required for therapeutic development in all mutant lines."

Amyotrophic Lateral Sclerosis • ANXA1 • ANXA11 • G3BP1 • TARDBP

Mutation-dependent stress pathway activation in ALS: Insights from VAPB P56S motor neurons (ALS-MND 2025) - "All phenotypes were evaluated over time in culture and under acute thapsigargin-induced ER stress...VAPB P56S-expressing MNs displayed reduced spontaneous neuronal firing, progressive mitochondrial depolarization, and disrupted ER-MAM ultrastructure. These neurons showed heightened sensitivity to ER stress, as evidenced by induction of ATF4 upon exposure to tunicamycin and suppression of protein synthesis. Similar findings were observed in ALS8 patient-derived MNs."

Amyotrophic Lateral Sclerosis • CNS Disorders • Metabolic Disorders • ATF4

SEC61B Regulates Calcium Flux and Platelet Hyperactivity in Diabetes Mellitus (ASH 2023) - "Calcium efflux from the ER was measured in the presence of translation inhibitors puromycin and eeyarestatin I and the sarcoendoplasmic reticulum calcium-ATPase inhibitor thapsigargin...Dysregulated SEC61B expression is associated with increased calcium efflux from the ER. We propose a mechanism whereby ER stress-induced upregulation of platelet SEC61B leads to increased cytoplasmic calcium, potentially contributing to the platelet hyperactivity seen in diabetes mellitus."

Cardiovascular • Coronary Artery Disease • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • APOE • ATF6 • EIF2A • EIF2S1 • ERN1 • SEC61G

Cerebral Spinal Fluid Attenuates the Efficacy of Methotrexate Against Acute Lymphoblastic Leukemia Cells (ASH 2023) - "While this was confirmed for several ALL drugs including cytarabine and anthracyclines, we strikingly found that methotrexate was significantly less efficacious and potent against ALL cells in CSF relative to standard tissue culture media or the more physiologically relevant human plasma-like media (HPLM). CSF also attenuated the sensitivity of ALL cells to other anti-folates including raltitrexed, trimetrexate, and pralatrexate...Activation of the UPR with thapsigargin, a sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) inhibitor that triggers ER stress, increased methotrexate resistance in leukemia cells...Moreover, we anticipate that our current work defining the mechanisms driving this resistance may identify novel approaches for maximizing methotrexate efficacy and more completely eradicating leukemia cells in CSF and the CNS. Finally, this work highlights the importance of critically evaluating even long-established standards of care."

Clinical • Acute Lymphocytic Leukemia • Central Nervous System Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia

APOL1 Variants Promote T Cell Excitation by Modulating Calcium (Ca2+) Signaling Downstream of T Cell Receptors (TCRs) in Graft Rejection (KIDNEY WEEK 2025) - "G1-CD8+T-cells had increases in delayed Ca2+ entry with TCR stimulation (+CD3) but reduced early cytosolic Ca2+ entry vs. G0s following addition of Thapsigargin, demonstrating pre-existing ER Ca2+ leak in G1-T-cells, a driver of store-operated calcium entry (SOCE)...SOCE inhibition (YM58483) or Ca2+ chelation (BAPTA) at low doses abolished increased proliferation observed in G1 mice, confirming the role of Ca2+ signaling in APOL1-mediated CD8+ T-cell activation. Conclusion We unravel an excitatory T-cell intrinsic mechanism for APOL1 exonic variants, causally linking them with kidney rejection."

IO biomarker • Chronic Kidney Disease • Transplant Rejection • CD8

DDX3X Promotes Multiple Myeloma Cell Survival and Proteasome Inhibitor Resistance through Modulation of Stress Granule Assembly and MAPKAPK2 Translation (ASH 2024) - "Furthermore, pharmacological inhibition of c-Myc with JQ-1 markedly reduced DDX3X mRNA and protein levels in MM cells...Moreover, DDX3X inhibition enhanced bortezomib or the ERS inducer thapsigargin (TG) -triggered apoptosis in MM cells...CONCLUSION In MM cells, DDX3X promotes cell survival and proteasome inhibitor resistance through modulation of stress granule assembly and MAPKAPK2 translation. Our findings suggest DDX3X as a promising therapeutic target in MM."

Hematological Malignancies • Multiple Myeloma • Oncology • ATF4 • CASP3 • DDX3X • G3BP1 • MAPKAPK2 • MYC • PABPC1

Interactions between Tau Phosphorylation and Endoplasmic Reticulum Stress in Diabetic Nephropathy. (PubMed, Diabetes Metab J) - "Transforming growth factor β-induced fibrosis or thapsigargin-induced ER stress increased tau phosphorylation, while inhibiting tau phosphorylation or ER stress alleviated mesangial cell damage...The interplay between tau phosphorylation and ER stress appears to contribute to disease progression. Targeting tau phosphorylation and its upstream stress pathways may offer new therapeutic strategies for DN."

Journal • CNS Disorders • Diabetic Nephropathy • Fibrosis • Immunology • Nephrology • Renal Disease • NOX5

GDF11 mitigates liver injury associated with pancreatitis by inhibiting endoplasmic reticulum (ER) stress and the activation of the TXNIP/NLRP3 inflammasome. (PubMed, Cell Signal) - "Using the ERS inducer thapsigargin (TG), we demonstrated that exogenous GDF11 targets ERS to modulate SAP-induced liver injury, involving ERS - associated oxidative stress and apoptosis. Additionally, exogenous GDF11 mitigates SAP-related liver injury by targeting the ERS/TXNIP/NLRP3 axis to regulate inflammatory responses."

Journal • Hepatology • Immunology • Inflammation • Liver Failure • Pancreatitis • Systemic Inflammatory Response Syndrome • GDF11 • NLRP3 • TXNIP