GLG-302 / GLG Pharma - LARVOL DELTA

Astragaloside IV attenuates oxidative stress-associated mitophagy-dependent ferroptosis in peritoneal mesothelial cells via suppression of STAT3 signaling. (PubMed, Front Pharmacol) - "In vitro, human peritoneal mesothelial cells (PMCs; HMrSV5) were assigned to different groups and exposed separately to PDF, carbonyl cyanide m-chlorophenylhydrazone, erastin, or colivlin, followed by separate treatment with N-acetylcysteine, mitochondrial division inhibitor 1, S3I-201, or AS-IV. Oxidative stress-associated, mitophagy-dependent ferroptosis contributes to PD-related peritoneal injury. AS-IV attenuates this process via suppression of STAT3 signaling in PMCs."

Journal • Fibrosis • Immunology

IL-22BP Attenuates Right Ventricular Remodeling in Pulmonary Arterial Hypertension. (PubMed, Clin Sci (Lond)) - "Pharmacological STAT3 inhibition with S3I-201 partially rescued the aggravated PAH and RV remodeling phenotype in SuHx-treated Il22ra2⁻/⁻ mice. Finally, treprostinil plus oridonin produced broader phenotypic improvement than either monotherapy and increased cardiac IL-22BP expression. These findings identify IL-22BP as a treatment-responsive endogenous regulator of PAH-associated RV remodeling."

Journal • Cardiovascular • Fibrosis • Hypertension • Immunology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • IL22

STAT3 inhibitor NSC74859 reduces inflammatory response while accumulates U-STAT3 with autophagy induction in HK-2 cells (ERA 2026) - "Conclusion Selective P-STAT3 suppression accompanied by U-STAT3 accumulation induces a distinct transcriptional reprogramming in HK-2 cells, enhancing autophagy while attenuating inflammatory STAT3 targets. These findings underscore the importance of distinguishing P-STAT3 and U-STAT3 when evaluating antifibrotic interventions."

Fibrosis • Inflammation • COL1A1 • EGR1 • IL6 • TGFB1 • TIMP1

The IL-6/JAK/STAT3 axis drives calcinosis in dermatomyositis via TNAP upregulation (SID 2026) - "Pharmacological blockade of the signaling cascade at the receptor (tocilizumab), kinase (tofacitinib), and transcription factor (S3I-201) level attenuated IL-6-induced TNAP upregulation. These results suggest that local IL-6 production drives calcinosis in DM through upregulation of TNAP, implicating the IL-6/JAK signaling pathway as a viable therapeutic target."

Dermatomyositis • Fibrosis • Immunology • Metabolic Disorders • Myositis • AEBP1 • EPAS1 • IL6 • SOD2 • TIMP1 • TIMP3

S3I-201, a STAT3 Inhibitor, Inhibits Proinflammatory Mediator Signalling in CD19 and CD45R/B220 Cells in a Mouse Model of Multiple Sclerosis. (PubMed, Cell Mol Neurobiol) - "S3I-201 inhibits the signalling of inflammatory mediators via various cellular pathways. Our findings suggest that S3I-201 may have therapeutic effects on EAE and may slow its progression in MS."

Journal • Preclinical • CNS Disorders • Immunology • Multiple Sclerosis • CSF2 • IL6 • NOTCH1 • NOTCH3

SMYD3-mediated H3K4 trimethylation aggravates hypertension-induced renal injury via TXNIP transcriptional activation. (PubMed, Int Immunopharmacol) - "SMYD3 was regulated by the JAK2/STAT3 pathway; STAT3 inhibitor S3I-201 reduced SMYD3 and H3K4me3, indicating that JAK2/STAT3 upregulates SMYD3 to exacerbate HRD. In conclusion, our findings demonstrate that SMYD3 acts as a key responsive mediator of Ang II-induced renal oxidative stress and inflammation, which is closely associated with the promotion of H3K4me3 enrichment at the TXNIP promoter. We also identify that the Ang II-activated JAK2/STAT3 axis may function as an upstream regulator of SMYD3 expression, thus providing novel insights and potential therapeutic targets for HRD."

Journal • Cardiovascular • Chronic Kidney Disease • Diabetes • Hypertension • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • NLRP3 • SMYD3 • TXNIP

Sphingosine-1-phosphate induces pulmonary artery smooth muscle cell proliferation, migration and pulmonary arterial remodeling by modulating sonic hedgehog signaling effector FoxM1. (PubMed, Chin Med J (Engl)) - "S1P/STAT3/Shh/Gli1/FoxM1 pathway plays an important role in PASMCs proliferation and pulmonary arterial remodeling. Targeting this cascade may have potential value for the management of PAH."

Journal • Brain Cancer • Cardiovascular • Glioma • Hypertension • Oncology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Solid Tumor • FOXM1 • GLI1 • SHH • SPHK1

Hepatoma-Derived Growth Factor Coordinates STAT3 Pathway and Exosome-Mediated Intrahepatic Crosstalk to Control Hepatic Steatosis and MASLD. (PubMed, Adv Sci (Weinh)) - "Consistently, pharmacological inhibition of STAT3 by S3I-201 abolishes HDGF-induced lipogenic gene expression and hepatic steatosis in mouse models...Together, these findings uncover a mechanism that couples hepatic lipogenesis to intrahepatic macrophage activation, driving both steatosis and inflammation in MASLD. Targeting the HDGF-STAT3 pathway and exosomal HDGF secretion may represent a potential therapeutic strategy for ameliorating metabolic dysfunction and hepatic inflammation in MASLD and related disorders."

Journal • Hepatocellular Cancer • Hepatology • Inflammation • Liver Cancer • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Solid Tumor • HDGF

Biomimetic exosome-delivered STAT3 inhibitor for radiosensitization in oral squamous cell carcinoma cells (AACR 2026) - "Our study presented an autologous exosome-based system for targeted STAT3 inhibitor delivery. Exo@S3I-201 significantly enhanced radiosensitivity in OSCC by inhibiting the STAT3 pathway, demonstrating its potential as a novel combination therapy to overcome radioresistance."

IO biomarker • Oncology • Oral Cancer • Squamous Cell Carcinoma

STAT3 inhibitor TTI-101 effectively intercepts bladder cancer in a carcinogen-induced rat bladder tumor model (AACR 2026) - "In the present study, we determined pharmacodynamic pSTAT3 inhibitory effect of STAT3 inhibiting small molecules (GLG-302, SH5-07, TTI-101) in-vitro BC cells and in-vivo rat tumors...(Project funded in whole with Federal funds from the NCI-NIH, DHHS, under Contract No. 75N91019D00020-75N91020F00005)."

Preclinical • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

Cardiomyocytes FGFBP1 induction by STAT3 drives pathological cardiac remodeling. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "Pharmacological inhibition of STAT3 using S3I-201 reduced FGFBP1 expression and recapitulated the protective effects observed in FGFBP1 KO mice. These findings establish FGFBP1 as a STAT3-dependent effector of pathological remodeling and highlight the STAT3-FGFBP1 axis as a potential therapeutic target."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • STAT3

Majoon Ushba alleviated IL-17A sensitized keratinocyte ferroptosis via JAK-2-STAT-3 signaling axis and reversed imiquimod induced psoriasiform inflammation. (PubMed, Pharm Biol) - "The STAT-3 inhibitor, S3I-201, was used to confirm the role of the STAT-3 axis in keratinocyte ferroptosis. Aligned with pre-clinical and in vitro results, the computational findings offer initial evidence that the polyherbal formulation may influence the IL-17A/JAK-2-STAT-3 signaling pathway. In conclusion, our preliminary findings reveal a plausible mechanistic basis for the anti-psoriatic efficacy of Majoon Ushba, warranting larger clinical trials in psoriasis patient cohorts."

Journal • Dermatology • Immunology • Inflammation • Psoriasis • GPX4 • IFNG • IL17A • IL17RA • IL23A • STAT3

The crosstalk between STAT3 and p53/ERK signaling regulates brain metastasis (AACR 2024) - "Human brain metastatic breast cancer cells (MDA-MB-231) were treated with STAT3 inhibitor (NSC74859) or MAPK inhibitor (U0126) in regular or astrocytic media to determine cell proliferation and migration by MTT assay and scratch-wound, respectively...These findings suggest activation of STAT3 and ERK1/2 promote BM and suppression of these pathways may lead to a reduction in cell viability and motility. Therefore, this provides compelling evidence for the use of STAT3 and ERK1/2 along with p53 as potential targets for immunotherapy in brain metastatic disease."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • PD-L1 • STMN1 • TP53

FUBP3-Mediated Recruitment of STAT3 Complex Formation to Activate EMT Factor Twist1 and Promote Lung Cancer Metastasis. (PubMed, Front Biosci (Landmark Ed)) - "This study reveals the critical role of FUBP3 in lung cancer metastasis and identifies a new regulatory axis involving FUBP3-STAT3-Twist1. FUBP3 interacts with STAT3, enhancing STAT3-dependent Twist1 expression, which promotes EMT and metastasis. FUBP3 functions as a prognostic biomarker, and STAT3 inhibitors present therapeutic strategies for lung cancer, offering novel insights for precision treatment."

Journal • Lung Cancer • Oncology • Solid Tumor • CDH1 • STAT3 • TWIST1 • VIM

Bone marrow tyrosine kinase on chromosome X promotes epithelial-mesenchymal transition through signal transducer and activator of transcription 3 in colorectal cancer. (PubMed, Int J Biol Macromol) - "Critically, the STAT3 inhibitor S3I-201 abrogated the pro-tumorigenic effects of BMX overexpression on HT29 cell proliferation, migration, and invasion. In conclusion, our findings establish that BMX drives CRC progression by activating STAT3 signaling pathway, which subsequently suppresses E-cadherin expression to induce EMT."

Journal • Colorectal Cancer • Oncology • Solid Tumor • BMX • CDH1 • CTNNB1 • STAT3

Targeting JAK2/STAT3-Dependent Macrophage Polarization by Chlorogenic Acid Attenuates Hepatic Inflammation in Chronic Stress. (PubMed, Cells) - "Chronic stress adversely affects and compromises physiological well-being in humans, inducing hepatic injury, with its pathogenesis mechanistically linked to alterations in macrophage polarization and the regulation of the inflammatory microenvironment. Additionally, the use of the JAK2/STAT3 signaling pathway inhibitor, S3I-201, demonstrated effects similar to those observed with CGA treatment. In summary, CGA modulates macrophage polarization and the inflammatory response through the regulation of the JAK2/STAT3 signaling pathway, thereby mitigating the liver injury induced by chronic stress."

Journal • Hepatology • Inflammation • Liver Failure • IL10 • IL1B • IL6 • JAK2 • STAT3 • TNFA

Jiedu Fang inhibits hypoxia-induced angiogenesis in hepatocellular carcinoma by targeting Aurora A/STAT3/IL-8 signaling pathway. (PubMed, J Integr Med) - "JDF exhibits efficacy in reducing hypoxia-induced angiogenesis in HCC through a mechanism involving the Aurora A/STAT3/IL-8 signaling pathway. Therefore, JDF holds promise as a potential therapeutic approach for targeting HCC angiogenesis. Please cite this article as: Zhong MF, Luo YJ, Guo YY, Xiang S, Lin WF. Jiedu Fang inhibits hypoxia-induced angiogenesis in hepatocellular carcinoma by targeting Aurora A/STAT3/IL-8 signaling pathway. J Integr Med. 2025; Epub ahead of print."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • ANGPT2 • AURKA • CD31 • CXCL8 • PECAM1

Membrane Tension Gates AT2 Fate Selection by Regulating FGF Signaling (ATS 2025) - "DPs were treated with small molecules, to rise CMT (CHIR22901 and Methyl Beta cyclodextrin; MBCD), inhibiting either endocytosis (Dynasore) or pathways downstream of FGF signaling (FR180204, Akt VIII, KRpep-2d, NSC 74859)... We found that CMT reduces immediately prior to alveolar differentiation, and that increasing CMT with CHIR and MBCD blocks differentiation of DPs in culture. As CMT reduces, we observe an increase in endocytosis and internalization of Fgfr2 in both cultured cells and in vivo at E17.5. Further, scRNAseq analysis showed an upregulation of ERK target genes and we have validated higher ERK activity in nAT2s in the reporter line."

Respiratory Diseases • FGF • FGFR2

JAK2/STAT3/HMGCS2 signaling aggravates mitochondrial dysfunction and oxidative stress in hyperuricemia-induced cardiac dysfunction. (PubMed, Mol Med) - "The JAK2/STAT3/HMGCS2 pathway may contributes to uric acid-induced cardiac dysfunction by affecting mitochondrial function, oxidative stress, and ATP metabolism, offering a potential therapeutic strategy for mitigating high uric acid-induced cardiac damage."

Journal • Cardiovascular • Metabolic Disorders • HMGCS2 • IL6

STAT3 Signaling Pathway in Health and Disease. (PubMed, MedComm (2020)) - "We systematically discuss therapeutic strategies, including JAK inhibitors (tofacitinib, ruxolitinib), Src Homology 2 domain inhibitors (S3I-201, STATTIC), antisense oligonucleotides (AZD9150), and nanomedicine-based drug delivery systems, which enhance specificity and bioavailability while reducing toxicity. By integrating molecular mechanisms, disease pathology, and emerging therapeutic interventions, this review fills a critical knowledge gap in STAT3-targeted therapy. Our insights into STAT3 signaling crosstalk, epigenetic regulation, and resistance mechanisms offer a foundation for developing next-generation STAT3 inhibitors with greater clinical efficacy and translational potential."

Journal • Review • Cardiovascular • CNS Disorders • Immunology • Oncology • IL6

Diabetes Advances Cardiomyocyte Senescence Through Interfering Rnd3 Expression and Function. (PubMed, Aging Cell) - "The STAT3 inhibitor S3I-201 blocked HG-induced STAT3 activation and mitigated cardiomyocyte senescence. These findings suggest that diabetes induces cardiomyocyte senescence via the miR-103a-3p/Rnd3/STAT3 signaling pathway, highlighting a potential therapeutic target for DCM."

Journal • Cardiomyopathy • Cardiovascular • Diabetes • Metabolic Disorders • Targeted Protein Degradation

STAT3 AND LOW-DENSITY NEUTROPHILS MEDIATED T LYMPHOCYTE SUPPRESSION IN CERVICAL CANCER PATIENTS (IPVC 2024) - "To these cultures, we added or not, the STAT3 inhibitor NSC74859. Our RNA data showed enrichment of pathways and processes related to neutrophil migration and activation, we also found, among the enriched pathways, about 30% of genes that had a STAT3 binding element in their promoter region... Low-density neutrophils with a immunosuppressor phenotype are found in cervical cancer patients. These cells can inhibit T lymphocyte activation, through STAT3 signaling. Our data points to yet another immunosuppressive mechanism dependent on STAT3 and potential therapy target."

Clinical • IO biomarker • Cervical Cancer • Oncology • Solid Tumor • CD69 • CEACAM8 • ITGAM • PD-L1 • STAT3

Enhanced anti-tumor efficacy of S3I-201 in breast cancer mouse model through Wharton jelly- exosome. (PubMed, Cancer Cell Int) - "Our results demonstrate that WJ-Exo is an effective carrier for targeting S3I-201 to tumor cells and enhances the therapeutic efficacy of S3I-201 in tumor-bearing mice."

IO biomarker • Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BCL2 • CASP3 • STAT3

Combining proteomics and Phosphoproteomics to investigate radiation-induced rectal fibrosis in rats and the effects of pSTAT3 inhibitor S3I-201 on human intestinal fibroblasts. (PubMed, J Proteomics) - "In our research, we utilized TMT labeling alongside LC-MS/MS techniques for an in-depth exploration of both proteomic and phosphoproteomic landscapes in rat models of radiation-induced intestinal fibrosis (RIRF). Our analysis shed light on the function and pathways of proteins and phosphorylated proteins triggered by radiation, as well as those offering protection against it. We mapped out a network of interactions within these proteins and validated the expression levels of key proteins through quantitative measures. Additionally, the study ventured into identifying STAT3 as a potential therapeutic target, evaluating the efficacy of the S3I-201 inhibitor in laboratory settings, and suggesting its utility for RIRF treatment. Overall, our findings provide groundbreaking insights into RIRF's underlying mechanisms, laying a solid foundation for developing future antifibrotic treatments."

Journal • Preclinical • Colorectal Cancer • Fibrosis • Gastrointestinal Cancer • Immunology • Oncology • Solid Tumor • CTGF • MYL9 • TGFB1

Influenza A virus infection activates STAT3 to enhance SREBP2 expression, cholesterol biosynthesis, and virus replication. (PubMed, iScience) - "Exogenous cholesterol reverses the inhibitory effect of S3I-201 and STAT3 deficiency on virus replication. STAT3 or JAK2 overexpression increases the expression of SREBP2 and its downstream target genes, leading to increased IAV replication. These observations collectively suggest that STAT3 activation facilitates IAV replication by inducing SREBP2 expression and increasing cholesterol biosynthesis."

Journal • Infectious Disease • Influenza • Respiratory Diseases • STAT3