thapsigargin / University of Nottingham, Pirbright Institute - LARVOL DELTA

CFTR correctors suppress Ca²⁺-cAMP signaling and cyst growth in primary cultures of ARPKD cholangiocytes. (PubMed, Cell Calcium) - "These changes were accompanied by profound remodeling of intracellular signaling, including elevated resting cytosolic Ca²⁺, an increased thapsigargin-releasable endoplasmic reticulum Ca²⁺ pool, increased STIM1 expression, reduced IP₃ receptor expression, a marked increase in intracellular cAMP, and a switch in adenylyl cyclase isoform expression characterized by increased AC3 and reduced AC6...Treatment with either VX-809 or VX-445 improved many of these abnormalities by increasing CFTR expression, partially restoring PC1 and PC2 expression, attenuating abnormal Ca²⁺ and cAMP signaling, reducing cholangiocyte proliferation and cyst growth, and shifting CFTR membrane distribution toward the WT pattern...These findings identify coordinated remodeling of Ca²⁺- and cAMP-dependent signaling as a central feature of ARPKD cholangiocytes and show that CFTR correctors are associated with improvement of multiple disease-associated pathways. Our results support..."

Journal • Cystic Fibrosis • Genetic Disorders • Hepatology • Immunology • Nephrology • Polycystic Kidney Disease • Pulmonary Disease • Renal Disease • Respiratory Diseases • CFTR • PKD1 • PKHD1 • STIM1

PhSAN induces PANoptosis via targeting RNF25-mediated endoplasmic reticulum stress. (PubMed, Cell Insight) - "When combined with thapsigargin (Tg), which further exacerbates ER stress beyond the adaptive threshold, this sustained and unresolved tumor-intrinsic stress signal triggers PANoptosis. Notably, the combination of PhSAN and bortezomib (BTZ) drives ER stress, synergistically activating PANoptosis and significantly inhibiting tumor growth in RCC. Our findings establish sustained and unresolved ER stress as a key upstream signal for PANoptosis induction and propose a novel therapeutic strategy for overcoming treatment resistance in RCC through pharmacological inhibition of RNF25 with PhSAN in combination with BTZ."

Journal • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Targeted Protein Degradation • EEF1A1

Inorganic polyphosphate chelates Ca2+ but cannot substitute for ATP as an energy source for SERCA. (PubMed, Biochem Biophys Rep) - "Unexpectedly, ADP, but not AMP, induced concentration-dependent, thapsigargin-sensitive Ca2+ uptake. Thus, polyP is a potent Ca2+ chelator but cannot substitute for ATP as an energy source for SERCA."

Journal

Assessing oxidative stress in retinal tissue using multispectral autofluorescence imaging. (PubMed, Free Radic Biol Med) - "These findings demonstrate that multispectral autofluorescence imaging captures stressor-specific signatures rather than a uniform oxidative stress phenotype. Importantly, robust classification performance using UV-free channels highlights the potential for clinical translation. Multispectral autofluorescence imaging therefore represents a promising non-invasive tool for assessing oxidative stress and metabolic dysfunction in retinal tissue."

Journal • Glaucoma • Metabolic Disorders • Ophthalmology

Beyond NAD Depletion: SARM1-Induced ATP Collapse Involves Direct ATP Degradation and Mitochondrial Dysfunction and Is Pharmacologically Reversible. (PubMed, Biology (Basel)) - "VER preserved NAD and ATP during SARM1 activation but failed to rescue FK866-mediated NAD starvation, thereby distinguishing CZ-48/SARM1-driven cytotoxicity from generic NAD depletion...ATPase-related perturbations, including thapsigargin and bafilomycin A1, also protected cells from CZ-48-induced death, further supporting a central role for ATP collapse in sarmoptosis. iTRAQ proteomics, MitoSOX Red staining, and DiOC6(3) staining revealed that CZ-48 treatment was associated with mitochondrial and metabolic remodeling, mitochondrial ROS accumulation, and mitochondrial depolarization, all of which were mitigated by VER. Collectively, these findings support a convergent ATP-collapse model in which SARM1 activation promotes NAD depletion, directly consumes ATP, and is associated with mitochondrial dysfunction that may amplify ATP-production failure."

Journal • Metabolic Disorders • CDC37 • HSP90AA1

Identification of NETs and inflammation-related prognostic genes in breast cancer and PCR experimental validation. (PubMed, Front Genet) - "Additionally, 18 drugs were considerably associated with the risk score, including six drugs such as Metformin and Thapsigargin, which could potentially be used to treat breast cancer. This study constructed a risk model and a nomogram for breast cancer prognosis using bioinformatics methods, and analyzed prognostic genes of breast cancer, which will be helpful to the improvement of breast cancer's outcome and the development of clinical medicine."

Journal • Breast Cancer • Oncology • Solid Tumor • CXCL13 • IL12B • SMYD3 • TFF1

Functional Proteomics and Biological Screening of Protein Misfolding Under ER Stress Conditions in a Neuroblastoma Cell Model. (PubMed, Curr Issues Mol Biol) - "This study investigates the cytoprotective efficacy and molecular targets of Vx-445 in Thapsigargin-induced ER stress in a neuronal cell model. These phenotypic modifications correlated with changes in proteomic expression and were validated by Drug Affinity Responsive Target Stability (DARTS) analysis to map restored cellular pathways and identify potential protein interaction partners. Together, these findings uncover alternative molecular targets for Vx-445, providing a mechanistic basis for drug repurposing strategies in endoplasmic reticulum stress-related diseases."

Journal • CNS Disorders • Neuroblastoma • Oncology • Proteinopathy • Solid Tumor

Activation phosphorylation and dephosphorylation dynamics of Ca2+/Calmodulin-dependent protein kinase Iα in HeLa cells. (PubMed, Cell Calcium) - "Histamine induced CaMKIα phosphorylation, peaking within 3-4 min; this process was abolished by treatment with either TIM-063 or intracellular Ca²⁺ chelation using BAPTA-AM and thapsigargin; however, not by extracellular Ca²⁺ depletion...Furthermore, co-expression of PP2Cα fully abolished ATP-, histamine-, or ionomycin-stimulated CaMKIα phosphorylation, which is consistent with in vitro dephosphorylation of CaMKIα at Thr177 by recombinant PP2Cα. Taken together, these results reveal that agonist-induced Ca²⁺ influx from the extracellular space or release from intracellular stores transiently activates CaMKK-CaMKIα signaling in HeLa cells, which is shut off by dephosphorylation catalyzed by PP2Cα as a promising candidate for CaMKIα phosphatase."

Journal

Targeting endoplasmic reticulum stress to attenuate cisplatin resistance in non-small cell lung cancer. (PubMed, Med Oncol) - "Using parental and cisplatin-resistant cell lines, we demonstrate that thapsigargin induces transcriptional responses consistent with endoplasmic reticulum stress, characterised by dynamic regulation of GRP78, PERK, XBP1, and ATF4 mRNA expression. Distinct UPR-related transcriptional patterns were observed between parental and resistant cells, suggesting adaptive remodelling of ER stress signalling during acquisition of cisplatin resistance. Collectively, these findings identify ER calcium homeostasis as a modifiable determinant of platinum responsiveness and support targeting ER stress pathways as a potential adjunct strategy to improve therapeutic efficacy in chemoresistant NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ATF4 • HSPA5 • XBP1

Pre-Existing Heterogeneity Predicts Rare Proteostasis-Stress Programs Across Diverse Perturbations. (PubMed, Biology (Basel)) - "Independent validation datasets provided external support for the inferred stress axes: tunicamycin and thapsigargin activated unfolded protein response/integrated stress response (UPR/ISR) modules in bulk RNA sequencing (RNA-seq), thapsigargin expanded populations with high X-box binding protein 1 (XBP1) UPR or activating transcription factor 4 (ATF4) ISR activity in donor-paired single-cell data, and an independent protocol-stress dataset indicated heat shock/proteostasis structure beyond cell type and quality control (QC). The resulting resource summarizes perturbation responses as activator protein 1 (AP1) immediate, UPR/ATF4, heat shock, replication-coupled and low/mixed dominant stress-program patterns. These findings suggest that stress variation should not be viewed solely as a nuisance covariate but may represent a predictable and biologically structured dimension of perturbation response space."

Heterogeneity • Journal • ATF4 • TCF4 • XBP1

The ubiquitin-activating enzyme inhibitor TAK-243 activates store-operated Ca2+ channels independently of endoplasmic reticulum Ca2+ stores and enhances mitochondrial Ca2+ buffering capacity in DU-145 human prostate cancer cells. (PubMed, Biochim Biophys Acta Mol Cell Res) - "Live-cell Ca2+ imaging with Fura2 showed that DU-145 cells exhibited spontaneous Ca2+ transients that were largely independent of the activity of the Na+/Ca2+ exchanger but were abolished by extracellular Ca2+ removal, La3+, Gd3+, BTP2 (Orai channel blocker), and thapsigargin (which depletes endoplasmic reticulum -ER- Ca2+ stores). They were also sensitive to U73122 (a phospholipase C inhibitor) and dantrolene (a ryanodine receptor blocker), suggesting the contribution of both store-operated Ca2+ channels and intracellular Ca2+ release pathways in the generation and maintenance of these Ca2+ spikes...TAK-243 also increased the membrane potential and the Ca2+ buffering capacities of mitochondria. Taken together, treating DU-145 cells with TAK-243 to prevent the ubiquitination of proteins activates the entry of Ca2+ through store-operated Ca2+ channels independently of the ER Ca2+ stores and alters mitochondrial functions."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • STIM1

Mechanism of Tougu Xiaotong Capsules in regulating miR-16-5p to alleviate cholesterol metabolic disorders in osteoarthritic chondrocytes (PubMed, Zhongguo Zhong Yao Za Zhi) - "A chondrocyte degeneration model was established by stimulating mouse chondrocytes with thapsigargin(TG)...Flow cytometry results confirmed that TGXTC mitigated the apoptosis of TG-induced chondrocytes. In conclusion, TGXTC can alleviate cholesterol metabolism disorders in osteoarthritic chondrocytes by regulating miR-16-5p."

Journal • Immunology • Metabolic Disorders • Osteoarthritis • Pain • Rheumatology • ABCA1 • APOA1 • CASP3 • MIR16

Autophagy prevents ER stress-induced Tight Junction barrier disruption via claudin-2 homeostasis. (PubMed, bioRxiv) - "In human intestinal epithelial Caco-2 monolayers, murine colon, and human colonic explants, induction of ER stress with tunicamycin, thapsigargin, or brefeldin A disrupted TJ barrier integrity, as demonstrated by reduced transepithelial electrical resistance and increased paracellular permeability. Finally, enteric rapamycin administration reduced ER stress and restored autophagy in murine DSS colitis. Collectively, these findings identify an IRE1α-AAK1-autophagy axis as a critical regulator of intestinal TJ barrier integrity during ER stress."

Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • AP2M1 • ATG7 • CLDN2 • OCLN

miR-20487-5p/SERCA1/MAPK/ERK Pathway Regulates Newt Limb Regeneration. (PubMed, Biology (Basel)) - "In the present study, we investigated the role and regulatory mechanism of SERCA1 during newt limb regeneration by using a limb-amputation model, shRNA-mediated knockdown, Thapsigargin-mediated SERCA1 inhibition, miRNAomics analysis, dual-luciferase reporter assays and Agomir therapy...Taken together, our study supports the significant role of the miR-20487-5p/SERCA1/MAPK/ERK axis in early newt limb regeneration. This study expands the current understanding of molecular mechanisms initiating newt limb regeneration."

Journal • MIR204

Dual modulation of intracellular Ca2+ signaling by hispidulin through endoplasmic reticulum mobilization and extracellular Ca2+ entry in human breast cancer cells. (PubMed, J Mol Histol) - "Thapsigargin-induced depletion of endoplasmic reticulum (ER) Ca2+ stores indicated that hispidulin mobilizes ER Ca2+, while phospholipase C (PLC) inhibition by U73122 completely abolished the [Ca2+]i increase. Collectively, these findings demonstrate that hispidulin regulates intracellular Ca2+ homeostasis via PLC-dependent ER Ca2+ release and extracellular Ca2+ influx through SOCE and nifedipine-sensitive Ca2+ entry components, leading to PKC activation. Enhanced cytotoxicity following Ca2+ chelation further underscores the importance of Ca2+ homeostasis in determining cellular responses to hispidulin."

Journal • Breast Cancer • Oncology • Solid Tumor

Synergistic Profiling of Programmed Cell Death and Immune Responses Identifies a Novel Prognostic Index for Cervical Cancer. (PubMed, ACS Omega) - "Profiling of drug susceptibility revealed that the high-risk cohort of patients showed resistance to rapamycin and idelalisib but were sensitive to thapsigargin and linsitinib. Overall, the ICDI shows strong potential as a prognostic marker for forecasting clinical outcomes and could facilitate personalized treatment strategies for CC patients."

Journal • Cervical Cancer • Oncology • Solid Tumor • FADD • MUC4

Human Foetal Neuroblasts Exhibit BK Channel-Dependent Membrane Voltage Oscillations upon Depolarization. (PubMed, Adv Sci (Weinh)) - "We previously described electrophysiological properties of primary neuroblast cultures isolated from the nucleus basalis of Meynert (hfNBMNs) of 12-week human foetuses, which possess the machinery for acetylcholine (ACh) synthesis, degradation and transport, functional muscarinic and nicotinic ACh receptors and tetrodotoxin- (TTX-) sensitive Na+ and K+ currents...This activity was sensitive to intracellular thapsigargin or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), as well as to extracellular tetraethylammonioum, Ba2+ or Iberiotoxin, thus indicating the involvement of big conductance Ca2+-activated K+ (BK) channel family. Our data demonstrate that hfNBMNs present recurrent, BK-dependent, high-frequency voltage waves which may reflect an immature excitability pattern involved in early neuronal maturation or cholinergic network integration within foetal basal forebrain, whose lack might lead to neurodevelopmental disorders as those associated..."

Journal • CNS Disorders • Developmental Disorders • Psychiatry

SRPRA affects hyperoxia-induced bronchopulmonary dysplasia by modulating endoplasmic reticulum stress through the CHOP pathway. (PubMed, J Cardiothorac Surg) - "SRPRA knockdown alleviates hyperoxia-induced AECII injury by attenuating CHOP-mediated ER stress. Our findings reveal the pathogenic role of SRPRA in BPD, and suggest SRPRA as a potential therapeutic target for this disease."

IO biomarker • Journal • Bronchopulmonary Dysplasia • Inflammation • Pulmonary Disease • Respiratory Diseases • BAX • BCL2

Phytochemical Profiling and Multitargeted Biological Activities of Crinum asiaticum L. var. anomalum Baker Leaf: In Vitro and In Silico Insights. (PubMed, Plants (Basel)) - "Furthermore, at non-cytotoxic concentrations (3.13 to 50 µg/mL), this fraction effectively rescued mouse β-TC6 insulinoma cells from thapsigargin...These findings demonstrate C. asiaticum L. var. anomalum Baker as a promising natural source for developing multitarget therapeutic agents against inflammation, diabetes, and cancer."

Journal • Preclinical • Diabetes • Hepatocellular Cancer • Liver Cancer • Metabolic Disorders • Oncology • Solid Tumor

Freeze-Dried Extracts of Eruca sativa Selectively Inhibit Nuclear Factor-κB and Vascular Endothelial Growth Factor Levels in Retinal Pigment Epithelial Cells. (PubMed, Prev Nutr Food Sci) - "Under thapsigargin (Tg) stimulation, ESF at 1 mg/mL significantly reduced VEGF expression and protein secretion by 32% and 34%, respectively...Collectively, the findings demonstrate that ESF selectively attenuates inflammatory and angiogenic responses by specifically inhibiting the NF-κB-VEGF axis. Dehydration, therefore, is a critical method determining ESF bioactivity, preserving native phytochemicals that confer focused anti-inflammatory and anti-angiogenic efficacy in RPE cells."

Journal • Age-related Macular Degeneration • Diabetic Retinopathy • Inflammation • Macular Degeneration • Ocular Inflammation • Oncology • Ophthalmology • Retinal Disorders • HSPA5 • IL1B • MAPK8 • TNFA • XBP1

Two-pore channel-2 controls calmodulin-dependent STIM1 inactivation. (PubMed, Nat Commun) - "TPC2 engagement triggered lysosomal Ca2+ release and mobilized ER Ca2+ stores but prevented RFP-STIM1 recruitment to the TIRF plane by thapsigargin and disassembled RFP-STIM1 clusters forming after store depletion, preventing and acutely reversing SOCE. These effects persisted in STIM1 mutants truncated after the SOAR and were prevented by TPC2 genetic or pharmacological invalidation, Calmodulin (CaM) inhibition, and cytosolic Ca2+ chelation. We conclude that Ca2+ ions released by TPC2 channels on lysosomes regulate CaM-dependent STIM1 inactivation."

Journal • STIM1

Echinacoside Attenuates Pathogenic α‑Synuclein Aggregation by Inhibiting the PERK–eIF2α–ATF3/CHOP Pathway in the PFFs Models of Parkinson’s Disease (EAN 2026) - "In vitro, PFFs-treated SH-SY5Y cells were exposed to the ER-stress inducer thapsigargin (Tg) or to ECH... ECH protects nigrostriatal dopaminergic neurons and reduces pathological α-Syn aggregation in PFFs-induced cellular and mouse models of PD, an effect closely associated with inhibition of PERK–eIF2α–ATF3–CHOP-mediated ER stress."

CNS Disorders • Movement Disorders • Parkinson's Disease • ATF3 • HSPA5

Structural Basis of SERCA Inhibition by Derivatives of di-tert-butylhydroquinone Revealed by X-ray Crystallography. (PubMed, J Membr Biol) - "Inhibitory potencies were determined in ATPase activity assays, and crystal structures of SERCA1a in complex with eight of the ten derivatives were obtained at resolutions of 2.6 Å or better, aided by co-crystallization of thapsigargin to stabilize the E2 state...Although no derivative exceeded BHQ in inhibitory activity, structural analysis suggests that repositioning hydroxy groups on the benzene ring or modifying alkyl substituents may further optimize binding affinity and thus inhibitory potency. Together, these results define the key molecular features of SERCA inhibition by BHQ analogs and suggest strategies for further optimization of this inhibitor class."

Journal • CD5

UPR/ATF4/Noxa pathway over-activation through SERCA2 inhibition or ONC201 treatment combined with ABT-737 triggers apoptosis in chemoresistant ovarian cancer cells and patient-derived tumor organoids (EACR 2026) - "Introduction: Ovarian cancer has a poor clinical prognosis due to chemoresistance following carboplatin/paclitaxel treatment...Material and The platinum-resistant cell line, OAW42-R, the HGSOC ovarian cell line OVCAR3 and patient-derived tumor organoids models (PDTO) were treated with anti-SERCA2 strategies (thapsigargin and siRNA targeting SERCA2) in presence of ABT-737.Result and Anti-SERCA2 strategies reverted the BCL-2 family member expression ratio in favour of pro-apoptotic proteins... Collectively, our study highlights that ABT 737, through BCL-xL inhibition and synergy with ER stress inducers, triggers ovarian cancer death, offering promising strategies for overcoming chemoresistance in relapsed ovarian cancer."

Clinical • IO biomarker • Oncology • Ovarian Cancer • Solid Tumor • ATF4 • BCL2 • BCL2L1

Notoginsenoside R1 Inhibits Porcine Deltacoronavirus Infection In Vitro by Restoring SERCA2-Mediated Calcium Homeostasis. (PubMed, Animals (Basel)) - "Thapsigargin, an inhibitor of SERCA2, showed similar antiviral capacity to NG-R1. Collectively, our findings suggest that NG-R1 exerts antiviral activity against PDCoV, potentially through regulation of calcium homeostasis mediated by SERCA2. This study provides a theoretical basis for the development of novel antiviral agents targeting calcium signaling pathways."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • KEAP1