belnacasan (VX-765) / Vertex - LARVOL DELTA

Potent Caspase-1 Antagonists From Dihydropyridine Derivatives: In Vitro Fluorescence Assays and Cell Imaging. (PubMed, ChemMedChem) - "THD, which exhibited comparable potency to the well-known inhibitor VX-765 (3.68 nM), was selected for further investigation...Western blot analysis of PMA-differentiated THP-1 cells further supported this observation by showing reduced cleaved IL-1β levels in the presence of THD. This inhibitory effect of THD on caspase-1 activity in a complex cell system was further confirmed by the concentration-dependent morphological changes in BMDMs."

Journal • Preclinical • Inflammation • CASP1 • IL1B

Bisphenol A aggravates colitis-associated intestinal epithelial injury: Mitochondrial dysfunction and CASP1-associated inflammatory signaling. (PubMed, Ecotoxicol Environ Saf) - "BPA aggravates colitis-associated intestinal epithelial injury and induces mitochondrial oxidative and bioenergetic dysfunction. CASP1-associated signaling contributes to, but does not fully account for, this epithelial response. Human single-cell data provide complementary context in IBD."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Metabolic Disorders • CLDN1 • IL1B • NLRP3 • PACERR • PTGS2 • TJP1

A New Mechanism of ox-LDL-Induced Endothelial Cell Pyroptosis. (PubMed, Int Heart J) - "SGK1 overexpression reversed the protective effect of Pyrrothiogatain. Mechanistic studies showed that SGK1 overexpression exacerbated ox-LDL-induced pyroptosis, while VX-765 significantly reversed this effect.This study elucidates that GATA3 activated SGK1 transcription by directly binding to its promoter region, thereby promoting Caspase1/GSDMD-dependent endothelial cell pyroptosis."

Journal • Atherosclerosis • Cardiovascular • Inflammation • CASP1 • GATA3 • GSDMD • NLRP3 • SGK1

Pharmaceutical therapies for pyroptosis in lung injury. (PubMed, Inflammopharmacology) - "Additionally, several synthetic small molecule drugs, including MCC950, disulfiram, VX765, and dimethyl fumarate, effectively intervene by binding to essential pyroptosis effector proteins...Although existing preclinical data substantiate the anti-injury efficacy of these agents, many candidate drugs encounter significant translational challenges, including low oral bioavailability, unstable metabolic profiles, and inadequate in vivo targeting specificity. This review aims to enhance our understanding of lung injury and pyroptosis while summarizing new therapeutic approaches and drugs, which hold significant implications for addressing the occurrence and progression of lung injury."

Journal • Review • Inflammation • Respiratory Diseases • NLRP3

Sugarcane Polyphenols Improve Depressive-like Behavior in CUMS Mice by Promoting the MAPK/ERK Signaling Pathway and Inhibiting NLRP3 Inflammasome Pyroptosis. (PubMed, Foods) - "Mechanistically, SP activates the MAPK/ERK pathway, which in turn suppresses NLRP3 inflammasome-mediated pyroptosis; this effect is attenuated by the MAPK/ERK inhibitor PD98059. Furthermore, SP synergizes with the caspase-1 inhibitor VX-765 to inhibit pyroptosis."

Journal • Preclinical • CNS Disorders • Depression • Inflammation • Psychiatry • NLRP3

Cardiotoxin from Naja atra Activates the NLRP3/Caspase-1/GSDMD Pyroptosis Pathway to Induce Skin Tissue Injury. (PubMed, PLoS Negl Trop Dis) - "CTX induces intracellular ROS accumulation that activates the NLRP3/caspase-1/GSDMD pyroptotic cascade as an important mechanism contributing to skin tissue necrosis through membrane pore formation and inflammatory amplification. Pharmacological inhibition (NAC, MCC950, VX-765) confirmed a hierarchical ROS → NLRP3 → caspase-1 → GSDMD cascade. The ROS-NLRP3-caspase-1-GSDMD axis constitutes a tractable therapeutic target for Naja atra envenomation."

Journal • Inflammation • GSDMD • IL18 • IL1B • NLRP3 • PYCARD • TLR4

A self-perpetuating neuron-intrinsic GSDMD-mtDNA-AIM2 inflammasome axis drives neuronal pyroptosis and cognitive impairment after traumatic brain injury. (PubMed, Front Immunol) - "Delayed pharmacological inhibition of caspase-1 (VX-765 applied 6 h after injury, after the first wave) selectively suppressed a discrete second wave of cytosolic mtDNA release at 9-12 h and attenuated late-phase LDH release, providing direct experimental evidence for a self-perpetuating second wave of mtDNA-driven AIM2 activation. These findings define a self-perpetuating, neuron-intrinsic GSDMD-mtDNA-AIM2 inflammasome-pyroptosis axis as a driver of TBI-CD, and identify neuron-targeted AIM2 silencing as a candidate therapeutic strategy for limiting post-TBI neuroinflammation and cognitive decline."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • Metabolic Disorders • Vascular Neurology • CA3 • CASP1

Crude Astragalus polysaccharides ameliorate cognitive impairment by preserving blood-brain barrier integrity and suppressing GSDMD-mediated pyroptosis in jellyfish-envenomed mice. (PubMed, Front Pharmacol) - "Mice were treated with APS, edaravone, or the Caspase-1-specific inhibitor VX-765...These findings indicate that APS protects against jellyfish venom-induced neurotoxicity mainly by preserving BBB integrity and suppressing canonical Caspase-1-dependent GSDMD-mediated pyroptosis. APS may therefore represent a potential therapeutic candidate for marine envenomation-associated neurological injury."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Hematological Disorders • Inflammation • Psychiatry • CLDN5 • IL18 • IL1B • MAPK8 • MMP9 • NLRP3 • OCLN • TJP1 • TNFA

Gasdermin D-dependent neutrophil pyroptosis exacerbates Coxsackievirus A6-induced neuroinflammation through NET formation. (PubMed, J Neuroinflammation) - "These findings enhance understanding of enteroviral pathogenesis, identify GSDMD as a promising therapeutic target, and provide a novel framework for developing precision interventions that reduce excessive inflammation without impairing essential host defenses."

Journal • CNS Disorders • Infectious Disease • Inflammation • Vascular Neurology • GSDMD • IL18 • IL1B • S100A8

Metrnl ameliorates ulcerative colitis by inhibiting NLRP3 inflammasome activation via ASC. (PubMed, Sci Rep) - "Cells with Metrnl interference or overexpression were intervened with three inflammasome activators (ATP, nigericin, or alum), and a caspase-1 inhibitor (belnacasan)...After Metrnl knockout, the colon of normal mice was shorter, and Metrnl-/- UC mice showed more severe colon tissue damage, reduced goblet cells, increased inflammation, and accumulation of pyroptosis protein expression, indicating that Metrnl knockout increases susceptibility to UC. Metrnl interferes with key inflammatory signaling pathways in UC by inhibiting the interaction between ASC and NLRP3, suggesting its potential in UC treatment."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • IL1B • NLRP3 • TNFA

The Neuroprotective Role of a Caspase-1 Inhibitor Against Apoptosis via Inhibition of Glial Hyperactivation in a Mouse Model of Epilepsy. (PubMed, J Integr Neurosci) - "These results indicate that inhibiting glial cell hyperactivation and neuroinflammation via caspase-1 inhibition may represent a potential therapeutic strategy for epilepsy."

IO biomarker • Journal • Preclinical • B Cell Lymphoma • CNS Disorders • Epilepsy • Inflammation • Lymphoma • Oncology • BAX • CASP1 • GSDMD • IL1B • IL6 • TNFA

Lycium barbarum glycopeptide confers neuroprotection in chronic ocular hypertensive rats: a study investigating visual function, retinal structure, microcirculation, and pyroptosis. (PubMed, Front Pharmacol) - "A COH rat model was established, and the animals were randomly assigned to model, LbGp, VX-765 (pyroptosis inhibitor), and VX-765+LbGp groups...These findings demonstrate that LbGp confers neuroprotection against COH-induced optic nerve injury, at least in part, through inhibition of the pyroptosis pathway. This study provides experimental evidence supporting LbGp as a potential therapeutic candidate for glaucoma."

Journal • Preclinical • Cardiovascular • Glaucoma • Ophthalmology

Nitroxoline attenuates sepsis-associated pancreatic injury through inhibiting NLRP3-inflammasome mediated pyroptosis. (PubMed, Toxicol Appl Pharmacol) - "The protective efficacy of NTX in the context of SPI was achieved via the regulation of pathological pyroptotic activation in both pancreatic acinar cells and macrophages, with the NLRP3-Caspase-1-GSDMD pyroptotic pathway serving as the key underlying molecular mechanism."

Journal • Infectious Disease • Septic Shock • IL18 • IL1B • IL6 • NLRP3 • TNFA

Pyroptosis in epilepsy: from pathophysiological mechanisms to therapeutic strategies. (PubMed, Front Cell Dev Biol) - "Clinically, the caspase-1 inhibitor VX-765 demonstrated favorable safety and preliminary efficacy in a Phase II randomized controlled trial in patients with refractory epilepsy; however, the trial did not meet its primary efficacy endpoint, suggesting that longer treatment durations may be required to assess its therapeutic potential. Preclinically, the GSDMD inhibitor disulfiram shows BBB-protective effects but is limited by off-target hepatotoxicity; conversely, development of the NLRP3 inhibitor MCC950 was discontinued following adverse hepatic findings in early clinical studies...Major translational hurdles poor CNS bioavailability of candidate inhibitors, compensatory activation of parallel cell death pathways, and the absence of validated, clinically actionable biomarkers. Future efforts should therefore focus on developing cell-selective pyroptosis modulators, advanced CNS-targeted delivery platforms (e.g., nanoparticle- or antibody-conjugated systems), and..."

Journal • Review • CNS Disorders • Epilepsy • Inflammation • CASP4 • GSDME • NLRP3 • TRPM7

Photodynamic therapy induces pyroptosis via GSDMD pathway in NCI-H226 human lung squamous carcinoma cells. (PubMed, Sci Rep) - "Notably, GSDMD silencing or caspase-1 inhibition with VX765 markedly abrogated PDT-induced pyroptosis. Collectively, PDT induces pyroptosis in NCI-H226 cells via the NLRP3-caspase-1-GSDMD axis. This study reveals a novel anti-tumor mechanism of PDT in LUSC, providing a theoretical basis and potential therapeutic targets for clinical LUSC management."

Journal • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma • GSDMD • IL18 • IL1B • NLRP3

Inflammasome Activation Limits Radiotherapy-Induced Antitumor Immunity and Shapes CD8⁺ Responses in a Sex-Dependent Manner (IMMUNOLOGY 2026) - "NLRP3 inflammasome activation limits RT-induced antitumor immunity by restricting CD8⁺ responses. VX765 enhances effector CD8+ T cell expansion and survival in males post-RT. Sex hormones modulate inflammasome activity, impacting efficacy of its blockade in combination with RT."

Oncology • Pancreatic Cancer • Solid Tumor • CD4 • CD8 • IL23A • MYD88 • NLRP3

Miltirone promotes pyroptosis via increasing pyroptosis-related protein NLRP3 and AIM2 in kidney renal clear cell carcinoma. (PubMed, Front Immunol) - "The enhancement of cell pyroptosis and the release of IL-1β and IL-18 cytokines were reversed by pretreatment with the pyroptosis inhibitor VX-765...Miltirone treatment inhibited KIRC cell proliferation and enhanced cell pyroptosis via the NLRP3/AIM2/GSDMD axis. This study provides a novel molecular mechanism and potential therapeutic targets in KIRC progression."

Journal • Clear Cell Carcinoma • Clear Cell Renal Cell Carcinoma • Oncology • Renal Cell Carcinoma • Solid Tumor • CASP3 • IL18 • IL1B • NLRP3

Antiseizure Medications that Did Not Reach the Epilepsy Market: An Assessment of Factors Contributing to Their Failed Clinical Development Over the Last Three Decades. (PubMed, Drugs) - "Compounds whose development was terminated include atimepazole, beprodone, cannabidivarin, carabersat, conantokin-G, dezinamide, elpetrigine, flunarizine, fluorofelbamate, ICA-105665, isovaleramide, JNJ-40411813, losigamone, naluzotan, padsevonil, pitolisant, ralitoline, remacemide, safinamide, soretolide, talampanel, tonabersat, T2000, T2007, valnoctamide, valrocemide, VX-765, zandatrigine, zuranolone, and 534U87. In some instances, failure to pursue an epilepsy indication could be explained by prioritization of development for other neurological or psychiatric conditions. This may reflect the perception of the drug market for common epilepsies being relatively crowded, and only attractive for compounds with outstanding safety or efficacy advantages over existing medications."

Journal • Review • CNS Disorders • Epilepsy • Psychiatry

ABT-737 efficiently inhibits hepatocellular carcinoma cell activity via regulating PANoptosis. (PubMed, Discov Oncol) - "ABT-737 exerts potent antitumor effects through the induction of PANoptosis in hepatocellular carcinoma, providing a promising therapeutic strategy for HCC treatment."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • ANXA5 • BAX • BCL2 • CASP3 • NLRP3 • RIPK1

Sublytic pyroptosis blocks Schwann cell remyelination through caspase-1-mediated Tyro3 cleavage. (PubMed, J Neuroinflammation) - No abstract available

Journal • CASP1

Innate immune signalling, neuroinflammation and network plasticity in temporal lobe epilepsy. (PubMed, Front Pharmacol) - "Targeted interventions-including TLR4 antagonists (TAK-242), IL-1-pathway inhibitors (anakinra; the caspase-1 inhibitor VX-765), NLRP3 inhibitors (MCC950), and complement-directed strategies-reduce seizure burden, mitigate hippocampal atrophy, and, when administered early, attenuate maladaptive network remodeling. Several conventional antiseizure medications, including levetiracetam, also exhibit immunomodulatory properties by modulating microglial activation, suggesting a mechanistic overlap between pharmacological seizure control and immune regulation...Achieving clinical translation will require immune-phenotype stratification, biomarker-guided timing of intervention, and advances in CNS-targeted delivery. Integrating immunomodulatory approaches with established antiseizure therapies offers a promising route toward disease modification, cognitive preservation, and more precise treatment of drug-resistant epilepsy."

Journal • Review • CNS Disorders • Epilepsy • Inflammation • Vascular Neurology • HMGB1 • IL1B • IL1R1 • IL6 • MYD88 • NLRP3 • TLR2 • TLR3 • TLR4 • TLR7 • TNFA

Deficiency of lysosomal TMEM175 in myeloid macrophages exerts anti-tumor immunity via inflammasome and cross-presentation pathway. (PubMed, Nat Commun) - "The anti-tumor immunity is abrogated by caspase-1 inhibitor VX-765, anti-IL-1β, and anti-IL-18...Finally, Tmem175-/- mice are more responsive to anti-PD-1. Our works implies TMEM175 to be a potential target for immunotherapy."

Journal • CNS Disorders • Oncology • CASP1 • CTSB • IL18 • IL1B • NLRP3

A Combination of VX765 and OLT1177 Reduced Brain Injury after Intracerebral Haemorrhage via Inhibiting Inflammasome Activation. (PubMed, Folia Biol (Praha)) - "Notably, the combination of OLT1177 and VX765 further attenuated brain injury after ICH by inhibiting inflammasome activation. The combination of OLT1177 and VX765 thus provided enhanced protection against brain injury by inhibiting inflammasome activation, suggesting that OLT1177 in combination with VX765 might serve as a promising therapeutic strategy for the treatment of ICH."

Journal • Cardiovascular • CNS Disorders • Inflammation • Vascular Neurology • CASP1 • IL1B • NLRP3

Amino-Modified Polystyrene Nanoplastics Induce Endothelial Pyroptosis and Pro-Atherogenic Cellular Responses. (PubMed, Food Chem Toxicol) - "The pyroptosis inhibitor VX-765 reduced PI-positive cells and the expression of pyroptosis proteins in HUVECs, supporting a critical role of pyroptosis in NH2-NPs-induced injury...These findings indicated that PS-NPs induced injury in HUVECs by NF-κB/NLRP3/GSDMD-mediated pyroptosis pathway and influenced THP-1 cells adhesion, migration, and foam cell formation. This study provided insights into the vascular toxicity mechanisms of PS-NPs and highlighted the critical role of surface chemical modifications in modulating their toxicological effects."

Journal • Acute Myelogenous Leukemia • Cardiovascular • Hematological Malignancies • Leukemia • Oncology • NLRP3

Pyroptosis in Peripheral Neuropathy: From Molecular Mechanisms to Therapeutic Targeting. (PubMed, CNS Neurosci Ther) - "Targeting pyroptosis is a novel therapeutic avenue for PN. This review synthesizes current mechanistic understanding, evaluates preclinical therapeutic strategies, and delineates crucial future directions, including elucidating gasdermin diversity, validating PANoptosis, and bridging the translational divide, thereby accelerating their application for patients suffering from PN."

Journal • Review • Neuroblastoma • Oncology • Pain • Peripheral Neuropathic Pain • Solid Tumor • CASP3 • CASP4 • CASP8 • GSDMC • GSDME • NLRP3