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

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

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

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

p-STAT3-elevated E3 ubiquitin ligase DTX4 confers the stability of HBV cccDNA by ubiquitinating APOBEC3B in liver. (PubMed, Theranostics) - "Approach & RNA-Seq analysis demonstrated that cucurbitacin I targeting STAT3 was associated with virus replication in liver...Our finding provides new insights into the mechanism of HBV cccDNA. The p-STAT3 and DTX4/MSL2 might serve as the therapeutical targets of HBV cccDNA."

Journal • Hepatitis B • Targeted Protein Degradation • APOBEC3B • DTX4 • IFNA1 • STAT3

Role of the JAK2/STAT3 pathway on infection of Francisella novicida. (PubMed, PLoS One) - "Among those inhibitors, we focused on cucurbitacin I, an inhibitor of the JAK2/ STAT3 pathway...In addition, treatment with these inhibitors destabilized actin filaments. These results suggest that the JAK2/STAT3 pathway plays an important role in internalization of F. novicida into host cells through mechanisms involving actin dynamics, such as phagocytosis."

Journal • Infectious Disease

Tumour growth inhibitory effect of Ibervillea sonorae phytopreparations in cervical cancer xenografts. (PubMed, Nat Prod Res) - "Cucurbitacin IIb, a triterpene obtained from the Ibervillea sonorae plant, reduces tumour development in a preclinical model of cervical cancer. Furthermore, only tumours treated with cisplatin showed invasion of bone tissue. The results show the potential use of I. sonorae phytopreparations in the treatment of cervical cancer."

Journal • Cervical Cancer • Oncology • Solid Tumor

Cucurbitacin I exerts its anticancer effects by inducing cell cycle arrest via the KAT2a-ube2C/E2F1 pathway and inhibiting HepG2-induced macrophage M2 polarization. (PubMed, Biochem Biophys Res Commun) - "In terms of regulation on tumor microenvironment, cucurbitacin I was demonstrated the ability to inhibit HCC cell-induced M2 polarization of macrophages. This comprehensive study unveils the multifaceted anti-cancer mechanisms of cucurbitacin I, providing robust support for its potential application in the treatment of HCC, offering new avenues for the future development of HCC treatment strategies."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Lymphoma • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2 • CASP3 • E2F1 • UBE2C

Nano-Selenium and Glutathione Enhance Cucumber Resistance to Botrytis cinerea by Promoting Jasmonic Acid-Mediated Cucurbitacin Biosynthesis. (PubMed, ACS Nano) - "Taken together, this study demonstrated that pretreatment of cucumber plants with SeG could activate the JA signaling pathway and promote cucurbitacin biosynthesis to enhance the resistance of the plants to B. cinerea infection. The findings also indicate that SeG is a promising biostimulant for protecting cucumber plants from B. cinerea infection without growth loss."

Journal • Infectious Disease

Plasmodium yoelii Infection Enhances the Expansion of Myeloid-Derived Suppressor Cells via JAK/STAT3 Pathway. (PubMed, J Immunol) - "By inhibiting STAT3 phosphorylation with the JAK inhibitor JSI-124, effects of serum on MDSCs are almost eliminated. In vivo depletion of MDSCs with anti-Gr-1 or 5-fluorouracil significantly reduces the parasitemia and promotes Th1 immune response in P. yoelii-infected C57BL/6 mice by upregulating IFN-γ expression. In summary, this study indicates that P. yoelii infection facilitates the accumulation and function of MDSCs by upregulating the expression of Bcl2 and Arg1 via JAK/STAT3 signaling pathway in vivo and in vitro. Manipulating the JAK/STAT3 signaling pathway or depleting MDSCs could be promising therapeutic interventions to treat malaria."

IO biomarker • Journal • Myeloid-derived suppressor cells • Infectious Disease • Malaria • Oncology • ARG1 • BCL2 • IFNG • IL6

Antihyperglycemic and antihyperlipidemic effects of fruit extract of Hodgsonia heteroclita (Roxb.) Hook. f. & Thomson in diabetic mice. (PubMed, J Ethnopharmacol) - "The present study demonstrated that ethanolic fruit extract of H. heteroclita improved both glycemic and lipid parameters in mice model of diabetes."

Journal • Preclinical • Diabetes • Dyslipidemia • Metabolic Disorders

Impact Of Wound Healing On Residual Tumors During The Perioperative Period: MRNA Sequencing Analysis In A Syngeneic Mouse Model (ESGO 2024) - "In the analysis using the REMEDY, MG-132, bortezomib, and cucurbitacin-i were predicted to effectively reduce mRNA changes one week after surgery, thereby enhancing the anti-tumor effect. Conclusion This study highlights the significant impact of wound healing processes on residual tumors in advanced ovarian cancer during the perioperative period."

Preclinical • Oncology • Ovarian Cancer • Solid Tumor

Biosynthetic pathway of prescription cucurbitacin IIa and high-level production of key triterpenoid intermediates in engineered yeast and tobacco. (PubMed, Plant Commun) - "This work uncovered the key genes involved in biosynthesis of prescription cucurbitacin IIa and constructed the engineered yeast cultivated with glucose to produce high-yield of key triterpenoid intermediates. We offered a low-cost and high-efficient platform for rapid screening candidate genes and high-yield production of pharmacological triterpenoids."

Journal • MAGEE1