cucurbitacin I (JSI-124) / H. Lee Moffitt Cancer Center and Research Institute, University of South Florida - LARVOL DELTA

Saxifraga umbellulata Attenuates Cholestatic Liver Injury and Modulates Farnesoid X Receptor-Related Bile Acid Homeostasis. (PubMed, Pharmazie) - "SU mitigated ANIT-induced cholestatic liver injury and promoted partial recovery of hepatic bile acid homeostasis. The protective effects of SU were associated with coordinated changes in hepatic and intestinal FXR-related signaling and with reduced inflammatory injury. These results provide experimental evidence supporting the traditional use of SU for hepatobiliary disorders and highlight cucurbitacin IIb and saxifragic acid as potential bioactive triterpenoids."

Journal • Cholestasis • Hepatology • Liver Failure • FGFR4

Anticancer Effects of Clausena hamandiana: Ethanolic Extract Inhibits Cancer Cell Proliferation and Suppresses Lung Tumorigenesis in Mice. (PubMed, Int J Mol Sci) - "Notably, 7-methoxyheptaphylline markedly suppressed STAT3 phosphorylation in a concentration-dependent manner, comparable to the STAT3 inhibitor JSI-124...Collectively, our results demonstrate that C. harmandiana exerts broad-spectrum anticancer activity through coordinated modulation of the JNK-STAT3 axis, leading to caspase-dependent apoptosis. These findings highlight its potential as a promising candidate for the development of STAT3-targeted anticancer therapies."

IO biomarker • Journal • Preclinical • Colorectal Adenocarcinoma • Colorectal Cancer • Hepatocellular Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1 • CASP3 • MCL1

Therapeutic Potential of Cucurbitacin I in Colon Adenocarcinoma Is Mediated by Modulation of SDHA Expression. (PubMed, J Cell Mol Med) - "Subsequent in vitro experiments demonstrated that CuI treatment upregulated SDHA expression and inhibited activation of the NF-κB pathway. Collectively, these findings suggest that the identified PBs may serve as early-warning indicators for stage I COAD patients and that CuI suppresses COAD cell proliferation, potentially through the SDHA/NF-κB axis, highlighting its promise as a potential therapeutic candidate."

Journal • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • SDHA

The downregulation of PEPCK mediated cuproptosis is involved in triclosan induced reproductive damage in mouse testes via triggering ROS overproduction. (PubMed, Free Radic Biol Med) - "Furthermore, inhibition of PEPCK and cuproptosis activation was rescued by reactive oxygen species (ROS) scavengers N-Acetylcysteine (NAC)...Drug prediction with Connectivity Map (cMap) identified flubendazole and cucurbitacin-i as a therapeutic drug. In conclusion, this study demonstrated that TCS triggered cuproptosis activation in TM4 cells mediated by ROS storm induced PEPCK inhibition. This research also shed new insight into precise treatment of TCS-related testicular injury."

Journal • Preclinical • PCK2

Multiomics analysis of Hemsleya ellipsoidea reveals genome evolution and specialized cucurbitacin IIa biosynthesis in a medicinal Cucurbitaceae species. (PubMed, Hortic Res) - "Collectively, this work provides the first high-quality genome of a medicinal Cucurbitaceae species and offers new insights into the chromosomal evolution, metabolic specialization, and adaptive diversification of H. ellipsoidea. The genomic resource also lays a foundation for functional genomics, metabolic engineering, and molecular breeding toward high-value triterpenoid production."

Journal

Multi-omics integration and machine learning reveal gut-immune signatures in idiopathic pulmonary fibrosis: insights from bulk RNA-seq, single-cell profiles, spatial transcriptomics, and experimental validation. (PubMed, Front Immunol) - "qPCR/ELISA in TGF-β1-stimulated fibroblasts, bleomycin mouse lungs, and patient plasma corroborated upregulation of IL33, CXCL13, IGF1 and downregulation of TLR4. Drug-signature reversal nominated cucurbitacin I and temsirolimus; molecular docking was performed as a preliminary in silico, computer-simulation-based assessment of potential ligand-protein interactions between these compounds and the four core targets. This study provides new insights into the importance of gut-immune-lung axis in IPF and identifies CXCL13, IL33, TLR4, and IGF1 as diagnostic signatures and therapeutic targets. By integrating public multi-omics resources with experimental validation, our findings offer a foundation for future diagnostic and treatment strategies aimed at modulating the gut microbiota and immune system in IPF."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CXCL13 • IGF1 • IL33 • TGFB1 • TLR4

Plasmodium yoelii infection induces lung injury by modulating type 2 conventional dendritic cells autophagy via the STAT3-IRF4 signaling. (PubMed, Cell Death Dis) - "Inhibition of STAT3 phosphorylation by the JAK inhibitor JSI-124 almost completely abolished the influence of Plasmodium on cDC2...IL-12 secreted by cDC2 drove Th1-biased T-cell differentiation, which exacerbated pro-inflammatory responses and increased immunopathological damage in lung tissues. Inhibition of STAT3 or knockout of IRF4 within cDC2 restored cDC2 autophagy, reduced aberrant accumulation, re-established the phagocytic function of cDC2, and attenuated pro-inflammatory responses of Th1 cells, ultimately alleviating lung inflammatory damage."

Journal • Asthma • Immunology • Infectious Disease • Inflammation • Malaria • Pulmonary Disease • Respiratory Diseases • CD4 • CDK1 • IL12A • IRF4 • TLR3

SOX4 dictates gastric cancer progression by modulating the tumor immune microenvironment (AACR 2025) - "RNA-seq analysis of SOX4 wildtype and knockout cells led to the identification of six drugs that could mimic the effects of SOX4 deletion, with Cucurbitacin-I and Tunicamycin emerging as potent inhibitors of GAC cell growth in patient-derived models. These findings highlight SOX4's role in driving GAC progression and immune evasion, offering potential therapeutic avenues for targeting SOX4 in GAC treatment."

Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor • SOX4

JAK2/STAT3-dependent regulation of MDM4/MDM2-p53 signaling in methotrexate-induced ferroptosis and nephrotoxicity. (PubMed, Arch Pharm Res) - "Importantly, either the knockdown of MDM4 or pharmacological inhibition of JAK2/STAT3 signaling pathway with JSI-124 partially attenuated MTX-induced ferroptosis, improved renal function indicators, and attenuated histopathological damage in vivo. Our findings demonstrate that MTX mediates phosphorylation-dependent activation of the JAK2/STAT3 pathway, which facilitates MDM4/MDM2 interaction to induce ferroptosis-associated nephrotoxicity. These findings support a role for JAK2/STAT3-MDM4/MDM2 signaling in MTX-induced ferroptosis and suggest that targeted inhibition of this axis may represent a potential nephroprotective strategy."

Journal • Acute Kidney Injury • Immunology • Nephrology • Oncology • Renal Disease • JAK2 • MDM4 • STAT3

Hydroalcoholic extract of Benincasa hispida (Thunb.) Cogn. reinstates renal structural and functional dynamics compromised in diabetic mice: molecular insights through integration of transcriptomics and proteomics. (PubMed, J Ethnopharmacol) - "The results of our investigation establish a scientific basis for the nephroprotective properties of Benincasa hispida in a mouse model of type 2 diabetes. The observed effects were associated with decreased genotoxicity and renal fibrosis, along with improved podocyte function."

Journal • Preclinical • CNS Disorders • Diabetes • Diabetic Nephropathy • Epilepsy • Fibrosis • Genetic Disorders • Immunology • Inflammation • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus • Urolithiasis • BCL3 • CD200 • CD2AP • HDAC1 • PARP1 • PODXL • S100A6 • TGFB1 • TPD52

Cucurbitacin I induces immunogenic cell death and synergistically potentiates cisplatin efficacy in epithelial ovarian cancer. (PubMed, Phytomedicine) - "CuI is a novel ICD inducer that elicits caspase-3/GSDME-mediated pyroptosis and boosts antitumor immunity in EOC. Notably, it enhances the chemosensitivity of EOC to CDDP, offering a promising strategy for EOC treatment."

IO biomarker • Journal • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • ANXA5 • CALR • CASP3 • CD8 • CD80 • CD86 • EGFR • GSDME • HMGB1 • PD-1

A Novel Transgenic Mouse Model of Down Syndrome Acute Lymphoblastic Leukemia Identifies Targetable Vulnerabilities (ASH 2023) - "We screened top candidate drugs in DS-ALL and non-DS ALL patient samples in vitro, and tested FK866 and cucurbitacin I in vivo in mice xenografted with a DS-ALL patient sample. We have generated the first de novo mouse model and cell lines recapitulating DS-ALL, which we have employed in drug screens to identify novel therapeutic approaches. These studies suggest promising candidates for further study in DS-ALL and other high-risk ALL subtypes to reduce toxicity and improve outcomes."

Preclinical • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Developmental Disorders • Genetic Disorders • Hematological Malignancies • Leukemia • Oncology • KRAS • NAMPT • PAX5

Pharmacokinetic Profile of Extracts from the Chayote (Sechium edule) H387 07 Hybrid and Phytochemical Characterization of Its Segregant H387 M16 for Potential Therapeutic Applications. (PubMed, Molecules) - "High-performance liquid chromatography (HPLC) identified polyphenols and cucurbitacins, notably cucurbitacin B (CuB) and cucurbitacin IIA (CuIIA), in the biological samples, and pharmacokinetic variables such as the maximum plasma concentration (Cmax), time to reach maximum concentration (Tmax), half-life (T1/2), and volume of distribution (Vd) were determined...Overall, these findings not only provide novel pharmacokinetic data for key metabolites of the H387 07 hybrid but also establish the phytochemical and antioxidant profile of its segregant H387 M16. This dual characterization strengthens the evidence of the therapeutic potential of Sechium genotypes and provides a valuable foundation for future studies aiming to develop standardized protocols and explore translational applications in drug development and natural product-based therapies."

Journal • PK/PD data • Hematological Malignancies • Leukemia • Oncology

Inflammopharmacological perspectives on plant-derived compounds: ınteraction with monkeypox virus receptors. (PubMed, Inflammopharmacology) - "Notably, Cucurbitacin I and Cucurbitacin E demonstrated the strongest affinities, surpassing Cidofovir. Detailed molecular interaction analyses revealed key binding residues (ALA2, ALA4, TRP24, ASP32, LEU101, THR133, ASN) within the receptor site. These phytochemicals are well known for their immunomodulatory and anti-inflammatory properties; therefore, their strong interactions with MPXV receptors may highlight a dual therapeutic potential-both in modulating host inflammatory responses and in providing a molecular basis for further exploration of phytochemical-based strategies in inflammation-associated viral pathologies."

Journal • Infectious Disease • Inflammation

Screening For Therapeutic Targets To Suppress GH Production And Proliferation In AIP Mutant GH-producing Cells (ENDO 2025) - "Cucurbitacin I downregulated POU1F1 expression at both mRNA and protein levels, suggesting that GH1 suppression is mediated through POU1F1 downregulation. These findings indicate the JAK2-STAT3 pathway and actin polymerization as potential therapeutic targets for drug-resistant, AIP-mutant pituitary tumors."

Late-breaking abstract • Acromegaly • Endocrine Cancer • Endocrine Disorders • Oncology • Pituitary Gland Carcinoma • CASP3 • CASP7 • GH1 • TSHB

Gene signature-guided isolation identifies cucurbitacins as STAT3 inhibitors from Picria fel-terrae Lour. (PubMed, Phytomedicine) - "With this study, we establish a novel approach for the isolation of function-specific bioactive compounds from the medicinal plant PFL, and identified cucurbitacins as potential STAT3-targeting antitumour agents."

Gene Signature • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CXCL10 • CXCL11

Chemical constituents from Ecballium elaterium and their cytotoxicity (PubMed, Zhongguo Zhong Yao Za Zhi) - "A total of 12 compounds were obtained, and they were identified according to the analysis of a variety of spectral data and literature comparison as 24Z-20,27-dihydroxy-16α,23α-epoxy-cucurbita-2-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside(1), cucurbitacin R(2), cucurbitacin B(3), cucurbitacin D(4), cucurbitacin I(5), cucurbitacin L(6), dehydrodiconiferyl alcohol(7), 3-hydroxy-4-methoxycinnamic acid(8), ferulaic acid(9), p-coumaric acid(10), rutin(11), and lariciresinol-4'-O-β-D-glucoside(12), among which compound 1 was a new compound. Compounds 2-6 had strong cytotoxicity against human lung carcinoma A549 cells with the IC_(50) values of(0.48±0.09),(0.03±0.002),(0.13±0.03),(0.87±0.14),(0.15±0.03) μmol·L~(-1), respectively, which were stronger than the positive control doxorubicin [IC_(50)=(3.92±1.60) μmol·L~(-1)]."

Journal • Lung Cancer • Oncology • Solid Tumor

Profiling and cheminformatics bioprospection of curcurbitacin I and momordin Ic from Momordica balsamina on α-amylase and α-glucosidase. (PubMed, J Enzyme Inhib Med Chem) - "A 140 ns simulation showed that cucurbitacin I (-63.06 kcal/mol) and momordin Ic (-66.53 kcal/mol) exhibited stronger binding to α-amylase than acarbose (-36.46 kcal/mol), whereas cucurbitacin I (-38.08 kcal/mol) and momordin Ic (-54.87 kcal/mol) displayed weaker binding to α-glucosidase, relative to acarbose (-63.73 kcal/mol). Generally, momordin Ic demonstrated better thermodynamic properties, hence further in vitro and in vivo studies are needed to validate their antidiabetic potential."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Anti-Inflammatory Regulatory Role of Signal Transducer and Activator of Transcription 3 Phosphorylation in Regulating Hypersensitivity Responses to Echinococcus granulosus Hydatid Cyst Fluid. (PubMed, J Inflamm Res) - "RBL-2H3 cells were cultured in vitro and sensitized with immunoglobulin E (IgE), followed by intervention with STAT3 inhibitors Stattic and JSI-124...Apoptosis assays revealed that both inhibitors caused varying degrees of cell damage (P < 0.01), potentially leading to late-stage apoptosis. Immunoblotting analyses confirmed that treatment with the two inhibitors reduced STAT3 phosphorylation levels at the S727 and Y705 sites, thereby inhibiting cell degranulation and alleviating immune responses."

Journal • Allergy • Immunology • STAT3

Cucurbitacin IIa Ameliorates DSS-Induced Ulcerative Colitis via Enhancing Intestinal Barrier Function and Inhibiting PERK/ATF4/CHOP Signaling Pathway. (PubMed, Turk J Gastroenterol) - "The results of qRT-PCR and immunofluorescence revealed that cucurbitacin IIa greatly elevated the expressions of ZO-1, claudin-1, occludin mRNA and protein. Cucurbitacin IIa dramatically ameliorates DSS-induced UC symptoms via suppressing the PERK/ATF4/CHOP pathway and reinforcing enteric barrier function."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • ATF4 • CLDN1 • IL1B • IL6 • MPO • OCLN • TJP1 • TNFA

Multifaceted Therapeutic Impacts of Cucurbitacin B: Recent Evidences From Preclinical Studies. (PubMed, Phytother Res) - "The most prevalent and bioactive cucurbitacin is Cucurbitacin B (CuB, C32H46O8), which is a tetracyclic triterpene chiefly present in the Cucurbitaceae family. CuB has a wide spectrum of pharmacological properties namely antioxidant, anticancer, hepatoprotective, anti-inflammatory, antiviral, hypoglycaemic, insecticidal, and neuroprotective properties, owing to its ability to regulate several signaling pathways, including the Janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3), AMP-activated protein kinase (AMPK), nuclear factor (NF)-κB, nuclear factor erythroid 2-related factor-2/antioxidant responsive element (Nrf2/ARE), phosphoinositide 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), Hippo-Yes-associated protein (YAP), focal adhesion kinase (FAK), cancerous inhibitor of protein phosphatase-2A/protein phosphatase-2A (CIP2A/PP2A), Wnt and Notch pathways. The present review highlights the medicinal attributes of Cucurbitacin B (CuB)..."

Journal • Preclinical • Review • Hepatology • Oncology • AMPK • CIP2A • STAT3

Cucurbitacin IIa Alleviates Colitis via Promoting the Release of Host-Derived Extracellular Vesicles Encapsulating microRNA-30b-5p. (PubMed, J Inflamm Res) - "In conclusion, cucurbitacin IIa appears to alleviate colitis by promoting the release of microRNA-30b-5p from host-derived extracellular vesicles. These findings enhance our understanding of cucurbitacin IIa's effects on intestinal health and offer potential new therapeutic targets for inflammatory bowel disease treatment."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • MIR30B

Cucurbitacin IIb mitigates concanavalin A-induced acute liver injury by suppressing M1 macrophage polarization. (PubMed, Int Immunopharmacol) - "CuIIb regulated M1 macrophage activation by modulating the nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways. Conclusively, these results demonstrated that CuIIb significantly prevented Con A-induced ALI by suppressing M1 macrophage polarization via the MAPK and NF-κB signaling pathways, demonstrating the potential use of CuIIb for ALI treatment."

Journal • Gastrointestinal Disorder • Hepatology • Inflammatory Bowel Disease • Liver Failure • Oncology • IL1B • IL6 • TNFA

Photobiomodulation reduces spinal cord edema by decreasing the expression of AQP4 in the astrocytes of male spinal cord injury rats via the JAK2/STAT3 signaling pathway. (PubMed, Photodiagnosis Photodyn Ther) - "These findings suggest that PBM reduces spinal cord swelling in rats after injury. This effect is associated with the inhibition of JAK2/STAT3 signaling pathway activation in astrocytes and the reduction in AQP4 expression."

Journal • Preclinical • CNS Disorders • Inflammation • Orthopedics • AQP4 • GFAP

Cucurbitacin IIb alleviates colitis via regulating gut microbial composition and metabolites. (PubMed, Heliyon) - "We further found that transplantation of fresh feces or heat-inactivated feces from mice treated with cucurbitacin IIb to DSS-treated mice alleviated colitis, similar to the effects of cucurbitacin IIb. Collectively, our results suggest that cucurbitacin IIb exerted anti-inflammatory effects in colitis by regulating the microbiota composition and metabolites, thereby alleviating colitis symptoms."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Transplantation • IL1B • IL6 • MPO