belnacasan (VX-765) / Vertex - LARVOL DELTA

Targeting gasdermin D-mediated pyroptosis: a precision anti-inflammatory strategy for acute and chronic lung diseases. (PubMed, Inflammopharmacology) - "In addition, we performed a systematic evaluation of emerging therapeutic interventions such as direct pore formation inhibitors (disulfiram and necrosulfonamide), upstream caspase inhibitors (VX-765), and anti-inflammatory phytochemicals (andrographolide, emodin, and baicalin). This review reports that GSDMD is a promising therapeutic target for acute and chronic inflammatory lung disease. This study provides new mechanistic contributions and translational approaches to augment targeted anti-inflammatory interventions in respiratory care by precise pyroptosis modulation."

Journal • Review • Acute Respiratory Distress Syndrome • Asthma • Chronic Obstructive Pulmonary Disease • Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CASP4 • IL18 • IL1B

Andrographolide-induced PANoptosis underlies its multiple organ toxicity in mice. (PubMed, Toxicol Appl Pharmacol) - "Consistent with this, Andro induced lytic cell death was markedly attenuated by caspase-1 inhibitor VX-765, pan-caspase inhibitors (IDN-6556, Z-VAD-FMK) and GSDMD/E inhibitor (disulfiram). In addition, RIPK1 inhibition (by Nec-1) partially reduced cell death, confirming RIPK1-dependent necroptosis as a minor contributor. In conclusion, our data establish PANoptosis as an important mechanism of Andro-induced organ injury, providing a mechanistic framework for Andro's dichotomous bioactivity, informing evidence-based dosing strategies to maximize therapeutic efficacy while mitigating toxicity risks in clinical practice."

Journal • Preclinical • CASP8 • GSDME • RIPK1

Targeting pyroptosis in atherosclerosis: emerging pharmacologic strategies and natural compound-based therapeutics-a narrative review. (PubMed, Int J Clin Pharm) - "Targeting pyroptosis offers a promising pharmacological approach for mitigating vascular inflammation and stabilizing atherosclerotic plaques. Natural compounds with inflammasome-modulating activities serve as valuable chemical scaffolds for the development of novel therapeutics. Further pharmacokinetic, toxicological, and clinical studies are needed to translate these mechanistic insights into effective treatment strategies for patients with atherosclerotic cardiovascular disease."

Journal • Review • Atherosclerosis • Cardiovascular • Inflammation • NLRP3

Dexmedetomidine Regulates HMGB1 Transferred by HK-2 Cell-Derived Exosomes to Suppress Myocardial Cell Pyroptosis by Activating the TLR4 Signaling Pathway. (PubMed, Ann Clin Lab Sci) - "Dex can significantly inhibit the expression of HMGB1 in HK-2 cell-derived exosomes exposed to H/R and inhibit AC16 cell pyroptosis through exosome uptake and the effect of HMGB1 on the TLR4 signaling pathway."

Journal • Cardiovascular • Reperfusion Injury • HMGB1

Impaired NLRP3 inflammasome signaling diverts pyroptotic to apoptotic caspase activation in macrophages. (PubMed, Front Immunol) - "Unexpectedly, VX-765 (a caspase-1 inhibitor) exhibited a pan-caspase inhibitor-like effect, suppressing caspase-8/-9/-3 activation and GSDME cleavage in a dose-dependent manner. Mitochondrial damage was observed in both WT and caspase-1-deficient cells upon nigericin stimulation, suggesting mitochondrial injury being an upstream event in this process. Collectively, our data indicate that NLRP3 inflammasome is poised to divert pyroptotic to apoptotic caspase activation for combating danger signaling when conventional pathway is impaired, highlighting a complex interaction between various forms of cell death pathways."

Journal • CASP8 • CASP9 • GSDME • NLRP3

Caspase-1 Inhibition Mitigates Neonatal Hyperoxia-Induced Vascular and Cardiopulmonary Inflammation in Neonatal Rats. (PubMed, Clin Sci (Lond)) - "Newborn rats randomized to room air (RA) or hyperoxia (85% O2) from postnatal (P) 1 to 14, received caspase-1 inhibitor, VX-765, or placebo...This was accompanied by reduced aortic stiffness and cardiac fibrosis, improved alveolar structure, pulmonary vascular density and vascular remodeling, and attenuation of right ventricular hypertrophy. Together, our findings suggest that inhibition of the caspase-1 pathway leads to decreased cardiopulmonary inflammation and remodeling.  In conclusion, targeting caspase-1 signaling may be a therapeutic strategy to prevent the consequences of vascular and cardiopulmonary inflammation associated with preterm birth and oxygen therapy."

Journal • Preclinical • Bronchopulmonary Dysplasia • Cardiovascular • Fibrosis • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • CASP1 • GSDMD • IL18 • IL1B

Caspase-1 Inhibition Ameliorates CAR T-Cell Apoptosis and Tumor Cell Pyroptosis to Enhance the Efficacy and Safety of CAR T-Cell Therapy (ASH 2024) - "We recently reported that sequential therapy with the CD19 monoclonal antibody tafasitamab and CD19-directed CAR T (CART19, 41BBζ costimulated) cells significantly ameliorated CAR T-cell apoptosis and tumor cell pyroptosis, improving CAR T safety and efficacy (PMID : 37879074)...Mice were treated 12 days later with cyclophosphamide (300 mg/kg, ip) and 24 hours after mice were imaged and randomized to receive 1 x 107, 1) untransduced T cell control (UTD), 2) mCART19 + vehicle control, or 3) mCART19 + VX765 (25 mg/kg)...VX765 also reduced tumor cell pyroptosis and CRS incidence without impacting CAR T anti-tumor activity in vivo. Given the favorable preclinical outcomes and existing clinical data on VX765, this approach holds substantial translational potential for enhancing the safety and efficacy of CAR T-cell therapy in patients with large B-cell lymphoma."

CAR T-Cell Therapy • Clinical • IO biomarker • Tumor cell • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ANXA5 • BCL2 • CASP1 • CASP3 • CASP7 • CCR7 • GSDME

Neutrophil Gasdermin D Pores as Potential Therapeutic Targets in APS-Associated Thromboinflammation (ACR Convergence 2025) - "In vitro, neutrophils were treated with inhibitors of GSDMD (disulfiram, necrosulfonamide) or caspase-1 (VX-765), followed by exposure to IgG fractions from controls or APS patients or affinity-purified anti-β2GPI. By releasing IL-1β, NETs, and other inflammatory mediators, GSDMD pores may play a crucial role in linking innate immunity to immunothrombosis in APS (Figure 1). Since GSDMD deficiency and inhibition (with repurposed agents like disulfiram) reduce neutrophil activation in APS models, targeting GSDMD could offer a new approach for managing inflammation-driven thrombosis that may not respond to anticoagulation alone."

Cardiovascular • Hematological Disorders • Inflammation • Thrombosis • IL18 • IL1B

Non-pyroptotic caspase-11 activity regulates osteoclastogenesis and pathological bone loss. (PubMed, Cell Death Differ) - "In addition, using the caspase-11 inhibitor, VX-765, substantially reduced ovariectomy-induced bone loss. These findings collectively reveal a novel, non-inflammatory function of caspase-11 in osteoclastogenesis, positioning it as a promising therapeutic target for osteolytic diseases."

Journal • Inflammation • Osteoporosis • CASP1

Targeting Caspase-1 in osteoarthritis: multi-omics insights into the effects of VX-765 on human chondrocyte function and phenotype. (PubMed, Front Immunol) - "The combined evidence supports VX-765 as a potential disease-modifying target for OA therapy. However, further investigation is warranted to clarify Caspase-1's physiological roles, including possible off-target effects of its inhibitors, in cartilage and other joint tissues and the clinical relevance of inter-individual variability, with genomic variants (e.g., rs61751523) as one potential contributor, for therapeutic application."

Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology • ABL1 • CASP1 • CTSD • IL1B • MMP13 • MRPS11 • SMAD2 • SOX9 • TNFA

Kynurenine facilitates renal cell carcinoma progression by suppressing M2 macrophage pyroptosis through inhibition of CASP1 cleavage. (PubMed, Open Life Sci) - "M2 macrophages were treated with pyroptosis inhibitor VX-765 or kynurenine to evaluate their effects on cell viability and pyroptosis...This study revealed that kynurenine inhibits pyroptosis in M2 macrophages via direct targeting of CASP1, creating a tumor-supportive microenvironment that accelerates RCC progression. These findings establish the kynurenine-CASP1 axis as a critical regulator of M2 macrophage pyroptosis and demonstrate its role in promoting RCC progression, identifying a potential therapeutic target for RCC treatment."

Journal • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CASP1

CASPASE INHIBITION IN HUNTINGTON'S DISEASE: A SYSTEMATIC REVIEW OF THERAPEUTIC STRATEGIES AND NEUROPROTECTIVE POTENTIAL (WCN 2025) - "Keywords included "Caspase inhibition," "Huntington's Disease," and "neuroprotection."A total of 215 articles were identified, and 40 studies were included Preclinical Studies:20 preclinical studies reported that caspase inhibitors, such as zVAD-fmk and VX-765, reduced apoptosis by [70]% and improved motor function by [65]%... Caspase inhibition demonstrates promising neuroprotective potential in HD, especially in preclinical models. However, clinical trials show mixed results, highlighting the need for further optimization and large-scale studies."

Review • CNS Disorders • Movement Disorders

Hepatocyte-derived extracellular vesicles promote endothelial dedifferentiation in chronic liver disease through the miR-153-3p - pyroptosis axis. (PubMed, Hepatology) - "HepEVs-derived miRNAs, particularly miR-153-3p, contribute to endothelial dysfunction in CLD by triggering pyroptosis through a paracrine mechanism. Inhibiting Caspase-1 may provide a novel therapeutic approach to mitigate endothelial dysfunction in CLD."

Journal • Cardiovascular • Fibrosis • Gastroenterology • Hepatology • Hypertension • Immunology • Inflammation • Liver Cirrhosis • Portal Hypertension • MIR200A • NOS3

Salinomycin promotes cell death via the activation of the ROS/NF-κB/NLRP3 pathway in cholangiocarcinoma. (PubMed, Neoplasma) - "Sal promoted an increase of Annexin-V positive cells in Huh-28 and RBE cells in a dose-dependent manner, which was efficiently inhibited by VX-765 (Caspase-1 inhibitor), while Sal-induced increase of ROS levels was partially inhibited by exposure to N-acetyl-L-cysteine (ROS scavenger). The activation of Sal on the ROS/NF-κB/NLRP3 pathway was also identified in CCA cells and tumor tissues. Collectively, these results suggested that Sal activated the ROS/NF-κB/NLRP3 pathway to promote pyroptosis-induced cell death in CCA and suggest it may be a promising treatment strategy for anti-CCA."

Journal • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • ANXA5 • NLRP3

Chlorogenic Acid and VX765 Alleviate Deoxynivalenol-Induced Enterohepatic Injury and Lipid Metabolism Disorders by Improving Intestinal Microecology. (PubMed, Toxins (Basel)) - "Retrograde endocannabinoid signaling was identified as a critical pathway for cecal microbial metabolism and hepatic lipid regulation mediated by CGA and VX765. Additionally, CGA and VX765 reversed the upregulation of IMPA, CDS2, DGKA, NDUFS8, and MAPK1 mRNA and protein expression levels induced by DON via the microbiota-gut-liver axis."

Journal • Dyslipidemia • Hepatology • Liver Failure • Metabolic Disorders • MAPK1

Curcumin exerts therapeutic effects on colorectal cancer by inducing pyroptosis through caspase‑1 activation. (PubMed, Mol Med Rep) - "In conclusion, curcumin may exert anti‑CRC effects by inducing caspase‑1‑mediated pyroptosis, highlighting its potential as a therapeutic agent. These findings suggest that curcumin could be integrated into current CRC treatment strategies, particularly in targeting pyroptosis to enhance tumor suppression."

Journal • Colorectal Cancer • Oncology • Solid Tumor • IL1B • NLRC5

USP7 overexpression prevents the progression of clear cell renal cell carcinoma by enhancing pyroptosis via TRIP12 deubiquitination. (PubMed, Cancer Biol Ther) - "The caspase-1 specific inhibitor, VX-765, partially abolished the anti-viability, and pro-pyroptosis effects of oe-USP7, indicating USP7 overexpression prevented the malignant phenotype of ccRCC cells by enhancing caspase-1 dependent pyroptosis...The similar effects of oe-USP7 on ccRCC development were found in ccRCC mice. USP7 mediated TRIP12 deubiquitination inhibited ccRCC progression by enhancing pyroptosis."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CASP1 • TRIP12 • USP7

A Potent Inhibitor of Caspase‑8 Based on the IL-18 Tetrapeptide Sequence Reveals Shared Specificities between Inflammatory and Apoptotic Initiator Caspases. (PubMed, ACS Bio Med Chem Au) - "Our findings reveal that VX-765, a known inhibitor of caspases-1 and -4, also inhibits caspase-8 (IC50 = 1 μM). Even when specificities are shared, the caspases exhibit different efficiencies and potencies for shared substrates and inhibitors. Altogether, we report the development of new tools that will facilitate the study of caspases and their roles in biology."

Journal • Infectious Disease • Inflammation • Respiratory Diseases • Tuberculosis • CASP8 • IL18 • IL1B

Impact of VX-765 and VX-740 on chondrogenesis and inflammatory cytokine release in murine micromass cultures. (PubMed, Connect Tissue Res) - "While an increase in anti-inflammatory cytokine levels was observed with VX-765, a decrease in pro-inflammatory cytokines was recorded in the case of VX-740 treatment. The results demonstrate the differential effects of the caspase-1 inhibitors VX-765 and VX-740 on chondrogenic cell cultures and point to molecules that may be potential targets for use in the local treatment of osteoarthritis."

Journal • Preclinical • Immunology • Osteoarthritis • Pain • Rheumatology • CASP1 • IL1B

Programmed cell death regulates hematopoietic cell homeostasis under radiation conditions. (PubMed, Stem Cell Res Ther) - "These data suggest that multiple programmed cell death pathways are involved in radiation-induced damage to hematopoietic cells. Inhibiting Caspase-1 activity can be used as a strategy for protecting against radiation-induced injury to hematopoietic stem cells."

Journal • Bone Marrow Transplantation • Transplantation

Inhibition of pyroptosis by belnacasan: A potential strategy for mitigating acute lung injury and multiple organ dysfunction. (PubMed, Tissue Cell) - "Belnacasan inhibits pyroptosis, reduces inflammation, and preserves organ morphology in ALI. These findings underscore its potential as a therapeutic agent for preventing multiple organ dysfunction in ALI."

Journal • Acute Lung Injury • Infectious Disease • Inflammation • Respiratory Diseases • CASP1 • CRP • IL1B

Tangzhiqing Exacerbates Oxidized Low-Density Lipoprotein-Induced Cell Pyroptosis Through Activation of NLRP3 Inflammasome in Human Umbilical Vein Endothelial Cells. (PubMed, Cell Biol Int) - "The inhibition of NLRP3-specific inhibitor MCC950 or caspase-1-specific inhibitor VX-765 effectively suppressed the expression of cellular pyroptosis-associated proteins. Our findings highlight the crucial role of Tangzhi Qing (TZQ) in regulating ox-LDL-induced pyroptosis and inflammation through the activation of the NLRP3 inflammasome. This suggests that NLRP3 inflammasome could serve as a promising therapeutic target for mitigating diseases associated with atherosclerosis."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • CASP1 • IL18 • IL1B • NLRP3

HUMAN PRIMARY MONOCYTES CELL DEATH AND IL-1ß PRODUCTION IS DIFFERENTLY REGULATED IN FMF PATIENTS COMPARED TO HEALTHY CONTROLS (EULAR 2025) - "Monocytes were incubated at 37⁰C, 5% CO 2 with 1 hour of medium, RIPK1 inhibitor (necrostatin-1 (nec-1)) (20 uM), caspase-1/4 inhibitor VX-765 (20 uM), or RIPK3 inhibitor GSK872 (25 uM), followed by 16 hours with caspase-8 inhibitor Z-IETD-FMK (10 uM), LPS (& nigericin) (5 ng/mL; 6.7 uM), TNFα & IFNγ (50 ng/mL; 50 ng/mL), or staurosporine (10 uM)... We were able to show that the classically known cell death pathways pyroptosis, apoptosis and necroptosis affect each other in human primary monocytes, thereby showing that cell death in human monocytes is a more complex network than previously described. Strikingly, caspase-8 inhibition alone in the absence of any other stimulus induced cell death and production of IL-1β in human primary monocytes, which was at least dependent on RIPK1 and RIPK3. Cell death induced by caspase-8 was even further increased in the presence of caspase-1/-4 inhibition, which in parallel showed a trend towards increased IL-1β production."

Clinical • Genetic Disorders • CASP8 • IFNG • IL1B • IL6 • RIPK1 • TNFA

Macrophage pyroptosis mediates hyperoxia-induced inflammatory lung injury in neonates. (PubMed, Front Immunol) - "Moreover, VX-765 also promoted cell proliferation and AT1 survival in the hyperoxia-exposed lung. NLRP3/Caspase-1/GSDMD-mediated pyroptosis plays a critical role in hyperoxia-induced neonatal lung injury, and targeting this pathway may be beneficial for the prevention of lung injury in preterm infants."

Journal • Bronchopulmonary Dysplasia • Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CD68 • GSDMD • IL1B • NLRP3 • PECAM1

Impact of NLRP6 Inflammasome on Neuroinflammation in Temporal Lobe Epilepsy. (PubMed, Neurochem Int) - "Administration of VX765 alleviated pathological alterations and exerted neuroprotective effects. These findings suggest that NLRP6 plays a critical role in the initiation and progression of epilepsy."

Journal • CNS Disorders • Epilepsy • Inflammation • IL18 • IL1B • IL6 • NLRP6