emricasan (IDN 6556) / Amerimmune - LARVOL DELTA

Integrated multiomics identifies inhibitors of apoptosis (IAPs) and death-inducing signaling complex (DISC) components as novel vulnerabilities to overcome immune evasion in TP53-inactivated Acute Myeloid Leukemia (ASH 2025) - "Notably, AML patients with TP53 mutations have limited benefit from standard inductionchemotherapy or from recently approved venetoclax-based combination regimens...We found that IAPinhibitors birinapant and tolinapant, as well as IAP PROTAC-degrader CST-626, potently sensitized TP53-inactivated AML to CAR-T/TCR-T and NK-92-mediated cytotoxicity...Pharmacological inhibition of thecaspase 8-cFLIP heterodimer with emricasan alone, or combined with IAP antagonists, effectivelyovercomes this checkpoint and sensitizes AML cells to immune cytotoxicity. These findings establish astrong preclinical rationale for combining cell death–promoting agents with T or NK cell–basedimmunotherapies to overcome immune resistance in TP53-mutated high-risk AML subset."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • BIRC2 • BIRC3 • CASP8 • FADD • TP53 • XIAP

Hyperthermia induces reductive stress in murine macrophages. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "Pharmacologic intervention revealed that pan-caspase inhibition by IDN-6556 abrogated the reductive stress and its consequences (ROS production, DNA damage, and mitochondrial injury), and suppressed the pyroptotic/apoptotic signaling and lytic cell death...Our study reveals that reductive stress-mediated Trx dysfunction, not oxidative stress, underlies HS-induced PANoptosis. Dual targeting of caspases and RIPK3 provides a novel therapeutic avenue against heat shock-associated diseases."

Journal • Preclinical • BCL2

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

Dietary choline-derived Trimethylamine N-oxide impairs hippocampal neuronal function via PANoptosis activation. (PubMed, NPJ Sci Food) - "Crucially, pharmacological co-inhibition of RIPK3 (GSK-872) and caspases (Emricasan) significantly rescued neuronal viability, confirming PANoptosis as the core pathogenic pathway. These findings establish a novel mechanistic link between a gut-derived metabolite and cognitive decline, identifying TMAO possesses neurotoxicity that drives neurodegeneration via PANoptotic cell death. Our work suggests that strategies targeting systemic TMAO levels may hold therapeutic potential for neurodegenerative disorders."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • IGF2BP1 • ZBP1

Opposing regulation of the K63-linked polyubiquitination of RIPK3 by SMURF1 and USP5 in necroptosis. (PubMed, Nat Commun) - "Reducing SMURF1, using a RIPK3 mutant defective in SMURF1-mediated ubiquitination, or overexpressing USP5 enhances necroptosis in leukaemia cells, leading to reduced tumour growth in xenograft models treated with birinapant and emricasan. These findings highlight the opposing regulation of K63-linked polyubiquitination of RIPK3 by SMURF1 and USP5 in necroptosis."

Journal • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • SMURF1 • USP5

Reprogramming of Pro-tumoral Monocyte-derived Macrophages: A Novel Strategy Targeting Cathepsin B and Non-Apoptotic Caspases (EACR 2025) - "Finally, we evidenced that targeting the CTSB / CASP8 axis with pharmacological agents (CA-074, Emricasan or our own original and specific non-apoptotic caspase inhibitors) or with genetic approaches (siRNA) not only inhibits the generation of anti-inflammatory macrophages but also reprograms them towards a pro-inflammatory profile. Our work identifies a novel CTSB / CASP8 axis as a key regulator of monocyte-to-macrophages differentiation and M2 polarization. By targeting this pathway, we have successfully reprogrammed anti-inflammatory macrophages to a pro-inflammatory state, providing novel therapeutic strategies to counteract immunosuppressive macrophages, reshape the tumor microenvironment and enhance anti-tumor immunity."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CASP8 • CSF1 • CTSB • IFNG • IL4

Safety and Effectiveness of Emricasan Versus Placebo in Patients With Nonalcoholic Fatty Liver Disease and/or Nonalcoholic Steatohepatitis: An Updated Systematic Review and Meta-Analysis. (PubMed, Am J Ther) - No abstract available

Journal • Retrospective data • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Andrographolide prevents necroptosis by suppressing the generation of reactive oxygen species. (PubMed, Acta Biochim Biophys Sin (Shanghai)) - "Our results demonstrate that Andro notably inhibits necroptosis in the in vitro cellular models induced by either lipopolysaccharide (LPS) plus IDN-6556 or a combination of TNF-α, LCL-161 (Smac mimetic) and IDN-6556. In contrast, derivatives, including dehydroandrographolide, neoandrographolide, 14-deoxy-11,12-didehydroandrographolide, and 14-deoxyandrographolide, have no anti-necroptotic effects and fail to upregulate Nrf2. Collectively, our findings demonstrate that Andro specifically inhibits the RIPK1/RIPK3/MLKL signaling axis to suppress necroptosis, highlighting its therapeutic potential against necroptosis-related disorders."

Journal • Inflammation • BCL2 • RIPK1 • TNFA

Theaflavin suppresses necroptosis by attenuating RIPK1-RIPK3-MLKL signaling and mitigates cisplatin-induced kidney injury in mice. (PubMed, Int Immunopharmacol) - "In this study, we found that theaflavin suppressed necroptosis in murine macrophages, MPC-5 podocytes and human HT-29 cells treated with TNF-α, Smac mimetic and IDN-6556 or LPS plus IDN-6556. In agreement with in vitro cellular data, theaflavin decreased the levels of phosphorylated MLKL, an in vivo biomarker for necroptosis, in macrophages and other cells in the kidney and the liver of mice with cisplatin-induced AKI. Collectively, these results indicate that theaflavin can suppress necroptosis by attenuating RIPK1/RIPK3/MLKL signaling and thereby conferring protection against cisplatin-induced AKI, uncovering a previously unappreciated action of black tea components against necroptosis-related disorders."

Journal • Preclinical • Acute Kidney Injury • Hepatology • Inflammation • Liver Failure • Metabolic Disorders • Nephrology • Renal Disease • Targeted Protein Degradation • RIPK1 • TNFA

Therapeutic Potential of Emricasan, a Pan-Caspase Inhibitor, in Reducing Cell Death and Extracellular Matrix Accumulation in Fuchs Endothelial Corneal Dystrophy. (PubMed, Cells) - "Transcriptome analysis revealed distinct gene expression changes in the corneal endothelium following emricasan treatment. These findings suggest that emricasan exerts dual protective effects by inhibiting caspase-7-mediated ECM accumulation and broadly suppressing apoptosis, highlighting its potential as a pharmacological therapy for FECD."

Journal • Ophthalmology • Transplantation • CASP7 • COL8A2 • TGFB1

Vascular Organoid Generation from Human-Induced Pluripotent Stem Cells. (PubMed, J Vis Exp) - "The modified protocol incorporates the use of microwells and the CEPT cocktail (chroman 1, emricasan, polyamines, and the integrated stress response inhibitor, trans-ISRIB) to improve embryoid body formation and cell survival. Differentiated, mature vascular organoids generated using this protocol are characterized by whole-mount 3D immunofluorescence microscopy to analyze their morphology and complex vasculature. This protocol enables the production of high-quality vascular organoids in a scalable manner, potentially facilitating their use in disease modeling and drug screening applications."

Journal

Pipeline of New Drug Treatment for Non-alcoholic Fatty Liver Disease/Metabolic Dysfunction-associated Steatotic Liver Disease. (PubMed, J Clin Transl Hepatol) - "Agents in this group include peroxisome proliferator-activated receptor agonists (e.g., pioglitazone, elafibranor, saroglitazar), bile acid-farnesoid X receptor axis regulators (obeticholic acid), de novo lipogenesis inhibitors (aramchol, NDI-010976), and fibroblast growth factor 21/19 analogs...Agents in this group include antioxidants (vitamin E), tumor necrosis factor α pathway regulators (emricasan, pentoxifylline, ZSP1601), and immune modulators (cenicriviroc, belapectin). The final group targets the gut (IMM-124e, solithromycin). Combination therapies targeting different pathogenetic pathways may provide an alternative to MASLD treatment with higher efficacy and fewer side effects. This review aimed to provide an update on these medications."

Journal • Review • Diabetes • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Type 2 Diabetes Mellitus • FGF21 • TNFA

Necroptosis-like cell death of infected DC contributes to protection against cutaneous leishmaniasis (ESDR 2024) - "C57BL/6 DC were infected with L. major w/ or w/o Emricasan (inhibits Caspase-8), Birinapant (inhibiting cIAP1/2), or Necrostatin-1 (blocks RIPK1). In contrast, IL-12p40 release is regulated independently of this cell death pathway. Our data shows that myeloid cell death, most likely DC necroptosis, is critical for the generation of protective immunity against L. major."

Dermatology • Infectious Disease • CASP8 • IL1A • IL1B • MYD88 • RIPK1

The caspase-inhibitor Emricasan efficiently counteracts cisplatin- and neomycin-induced cytotoxicity in cochlear cells. (PubMed, J Mol Med (Berl)) - "Sodium thiosulfate and Emricasan provide similar protective effects to cisplatin-treated cells. Emricasan is more potent than sodium thiosulfate in reducing neomycin-induced cytotoxicity."

Journal • Oncology • Otorhinolaryngology • Solid Tumor

Necroptosis in recurrent implantation failure: A bioinformatics analysis of key genes and therapeutic targets. (PubMed, Medicine (Baltimore)) - "Several drugs targeting CASP1, such as nivocasan and emricasan, were identified as potential treatments. The study sheds light on the role of necroptosis in RIF, identifying key genes and immune alterations that could serve as biomarkers and therapeutic targets. These findings pave the way for future experimental research and clinical applications targeting necroptosis in RIF treatment."

Journal • BIRC3 • CASP1 • FASLG • TLR3 • XIAP

Multisite studies for optimization of a highly efficient culture assay used for in vitro detection of residual undifferentiated human pluripotent stem cells intermingled in cell therapy products. (PubMed, Regen Ther) - "The efficiency of colony formation was significantly higher under culture conditions with the combination of Chroman 1, Emricasan, Polyamines, and Trans-ISRIB (CEPT) than with Y-27632, which is widely used for the survival of hPSCs...The sorting efficiency of microbeads conjugated with the anti-Tra-1-60 antibody was sufficiently higher (>80%) than those of the other various microbeads investigated. Results of these multisite studies are expected to contribute to improvements in the sensitivity and robustness of the HEC assay, as well as to the future standardization of the tumorigenicity risk assessment of hPSC-derived CTPs."

Journal • Preclinical • Oncology

Polyethylene Glycol and Caspase Inhibitor Emricasan Alleviates Cold Injury in Primary Rat Hepatocytes. (PubMed, Cryobiology) - "We show the addition of 5% PEG to the storage medium significantly reduced the release of lactate dehydrogenase (LDH) in plated rat hepatocytes and a combinatorial treatment with emricasan maintains hepatocyte viability and morphology following recovery from cold storage. These results show that cold-stored hepatocytes undergo multiple mechanisms of cold-induced injury and that PEG and emricasan treatment in combination with supercooling may improve cell and organ preservation."

Journal • Preclinical • Transplantation

The positive feedback loop of the NAT10/Mybbp1a/p53 axis promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury. (PubMed, Redox Biol) - "The inhibition of cardiomyocyte ferroptosis by Fer-1 exerted superior cardioprotective effects against the NAT10-induced exacerbation of post-I/R cardiac damage than the inhibition of apoptosis by emricasan...Moreover, knockdown of Mybbp1a partially abolished the detrimental effects of NAT10 overexpression on cardiomyocyte ferroptosis and cardiac I/R injury. Collectively, our study revealed that p53 and NAT10 interdependently cooperate to form a positive feedback loop that promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury, suggesting that targeting the NAT10/Mybbp1a/p53 axis may be a novel approach for treating cardiac I/R."

Journal • Cardiovascular • Coronary Artery Disease • Myocardial Ischemia • Reperfusion Injury • NAT10 • SLC7A11

Small Molecules for the Treatment of Long-COVID-Related Vascular Damage and Abnormal Blood Clotting: A Patent-Based Appraisal. (PubMed, Viruses) - "Treatments for COVID-19 include antiplatelet (e.g., aspirin, clopidogrel) and anticoagulant agents, but their impact on morbidity and mortality has not been proven. By retrieving patent literature published in the last two years, small molecules patented for long-COVID-related blood clotting and hematological complications are herein examined, along with supporting evidence from preclinical and clinical studies. An overview of the main features and therapeutic potentials of small molecules is provided for the thromboxane receptor antagonist ramatroban, the pan-caspase inhibitor emricasan, and the sodium-hydrogen antiporter 1 (NHE-1) inhibitor rimeporide, as well as natural polyphenolic compounds."

Adverse events • Journal • Cardiovascular • CNS Disorders • Coronary Artery Disease • Heart Failure • Hematological Disorders • Infectious Disease • Ischemic stroke • Novel Coronavirus Disease • Thrombosis • Vascular Neurology • Venous Thromboembolism

A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. (PubMed, J Hepatol) - "Emricasan treatment did not improve liver histology in subjects with NASH fibrosis despite target engagement and may have worsened fibrosis and ballooning. Caspase inhibition lowered serum ALT in the short-term but may have directed cells to alternative mechanisms of cell death, resulting in more liver fibrosis and hepatocyte ballooning."

Clinical • Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Biomaterials Functionalized with Inflammasome Inhibitors-Premises and Perspectives. (PubMed, J Funct Biomater) - "Pharmaceutical substances can control the inflammasomes by three mechanisms: inhibiting the intracellular signaling pathways (Allopurinol and SS-31), blocking inflammasome components (VX-765, Emricasan and VX-740), and inhibiting cytokines mediated by the inflammasomes (Canakinumab, Anakinra and Rilonacept). Moreover, phytochemicals inhibit the inflammasomes by neutralizing reactive oxygen species. Biomaterials functionalized by the adsorption of therapeutic agents onto different nanomaterials could represent future research directions to facilitate multimodal and sequential treatment in oral pathologies."

Journal • Review • Dental Disorders • Immunology • Inflammation • Periodontitis

Identification of apoptosis-related gene signatures as potential biomarkers for differentiating active from latent tuberculosis via bioinformatics analysis. (PubMed, Front Cell Infect Microbiol) - "Furthermore, 24 drugs, including progesterone and emricasan, were predicted. The correlation analysis revealed that biomarkers were positively correlated with most m6A or m5C regulators. The six ARGs can serve as effective biomarkers differentiating ATB from LTBI and provide insight into the pathogenesis of Mycobacterium tuberculosis infection."

Biomarker • Gene Signature • Journal • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • Tuberculosis • ATF3 • CASP1 • CASP4 • CASP5 • IFI16 • TNFSF10

Emricasan for the treatment of liver cirrhosis: a meta-analysis of randomized controlled trials. (PubMed, Afr Health Sci) - "Overall, compared with control group for liver cirrhosis, emricasan treatment had no substantial impact on MELD (SMD=-0.19; 95% CI=-0.44 to 0.06; P=0.14), INR (SMD=0.12; 95% CI=-0.13 to 0.37; P=0.36), total bilirubin (SMD=-0.27; 95% CI=-0.56 to 0.01; P=0.06), serum albumin (SMD=0; 95% CI=-0.25 to 0.25; P=1.00) or adverse events (OR=1.35; 95% CI=0.56 to 3.24; P=0.50). Emricasan treatment provided no benefit for the treatment of liver cirrhosis."

Journal • Retrospective data • Review • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis

Caspase cleavage of RIPK3 after Asp is dispensable for mouse embryogenesis. (PubMed, Cell Death Differ) - "Ripk3 macrophages died at the same rate as wild-type (WT) macrophages in response to TNF plus cycloheximide, TNF plus emricasan, or infection with murine cytomegalovirus (MCMV) lacking M36 and M45 to inhibit caspase-8 and RIPK3 activation, respectively. We conclude that caspase cleavage of RIPK3 is dispensable for mouse development, and that cleavage of caspase-8 substrates, including RIPK1, is sufficient to prevent necroptosis."

Journal • Preclinical • Cytomegalovirus Infection • Infectious Disease • Oncology • CASP3 • CASP8 • RIPK1 • TNFA

Stress-free cell aggregation by using the CEPT cocktail enhances embryoid body and organoid fitness. (PubMed, Biofabrication) - "Application of CEPT (chroman 1, emricasan, polyamine, trans-ISRIB) for just 24 hours during cell aggregation has long-lasting consequences affecting morphogenesis, gene expression, cellular differentiation, and function. Various qualification methods confirmed that CEPT treatment enhanced experimental reproducibility and consistently improved EB and organoid fitness as compared to the widely used ROCK inhibitor Y-27632. Collectively, we discovered that stress-free cell aggregation and superior cell survival in the presence of CEPT are critical quality control determinants that establish a robust foundation for bioengineering complex tissue and organ models.&#xD."

Journal • Developmental Disorders