LY2109761 / Eli Lilly - LARVOL DELTA

Multi-Omics Integration Identifies a Five-Gene Metabolic Signature With Experimental Validation in Clear Cell Renal Cell Carcinoma. (PubMed, Cancer Rep (Hoboken)) - "This study establishes a precision oncology framework for ccRCC by functionally linking metabolic biomarkers, immunophenotypes, and stratified therapeutic strategies. Importantly, we identify SUCLA2 as a potential functional tumor suppressor and a promising target for further mechanistic and translational investigation."

Biomarker • Journal • Tumor mutational burden • Clear Cell Renal Cell Carcinoma • Dyslipidemia • Genito-urinary Cancer • Metabolic Disorders • Oncology • Solid Tumor • ACAT1 • HMGCS2 • TMB

Intraocular pressure reduction attenuates form-deprivation myopia by modulating scleral extracellular matrix remodeling via the TGF-β1/Smad signaling pathway. (PubMed, Exp Eye Res) - "Intraocular pressure reduction achieved separately via two mechanistically distinct pharmacological approaches mitigates FDM by preserving scleral integrity through modulation of ECM remodeling, an effect mediated via activation of the TGF-β1/Smad signaling pathway."

Journal • Ophthalmology • MMP2 • SMAD3 • TGFB1 • TIMP2

A novel lncPEAN inhibits the proliferation, invasion and migration of trophoblasts via WDR74/TGF-β1/Smad pathway. (PubMed, Cell Signal) - "Rescue experiments demonstrated that WDR74 knockdown or treatment with the TGF-β receptor inhibitor LY2109761 reversed lncPEAN-mediated suppression of trophoblast proliferation, invasion, and migration. Collectively, these findings indicate that lncPEAN silencing alleviates preeclampsia progression and rescues the dysfunctional trophoblast phenotype by targeting the WDR74/TGF-β1/Smad axis, highlighting its potential as a diagnostic biomarker for the onset of preeclampsia."

Journal • Gynecology • TGFB1

Targeting microglial MyD88 reprograms injury-activated microglia and promotes spinal cord repair via TGF-β signaling and biomimetic nanodelivery. (PubMed, Theranostics) - "TGF-β receptor blockade with LY2109761 abolished the protective effects of MyD88 deficiency. Additionally, ST2825·DSPE@MG nanoparticles exhibited microglia-targeted uptake and conferred superior therapeutic efficacy. Our data establish MyD88 as a critical regulator of microglial reprogramming after SCI and highlight its potential as a therapeutic target for spinal cord repair."

Journal • CNS Disorders • Inflammation • Orthopedics • MYD88 • TGFB1

Cell pellets promote periodontal bone regeneration in furcation involvement by regulating macrophage polarization through TGF-β1 secretion. (PubMed, BMC Oral Health) - "This study provides a novel scaffold-free therapeutic option for furcation involvement, addressing the clinical bottleneck of insufficient immunomodulation and limited regenerative efficacy of traditional treatments. The TGF-β1-mediated immunomodulatory and regenerative effects of cell pellets offer a promising approach to improve functional periodontal tissue restoration and tooth preservation in clinical practice."

Journal • Dental Disorders • Immunology • Inflammation • Periodontitis • TGFB1 • TGFBI

Effect of LY2109761 on TGF-β1/TGFβRI/Smad Pathway and Hepatic Fibrosis Cysts Formation in Rats Infected with Echinococcus granulosus: an In Vitro and In Vivo Study. (PubMed, Acta Parasitol) - "TGF-β1 acts on HSC surface, where it binds to TGF-βRI to stimulate the production of hepatic fibrosis cysts via TGF-β1/TGFβRI/Smad. Blocking TGF-β1 linking to the TGFβRI receptor can lessen PSCs damage to liver cells, prevent fibrotic cyst formation, and activate the immune system in the body to kill invaders."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Infectious Disease • Liver Cirrhosis • IL10 • IL13 • IL17A • IL1B • IL2 • IL4 • IL5 • IL6 • TGFB1

Intranasal administration of transforming growth factor beta 1 and its effect on the monoaminergic neurons in the rat brain (CINP 2026) - "Recent studies have explored its involvement in the central nervous system, particularly in the therapeutic effect of arketamine, the (R)-enantiomer of ketamine, which exhibits rapid and sustained antidepressant action with fewer dissociative side effects than ketamine (Wei et al., Mol Psychiatry 27:559, 2022)... Adult male Wistar rats weighing 250-350g were briefly sedated with isoflurane and intranasally administered TGF-β1 (0,01 mg/kg) or vehicle...To assess whether the putative effect of TGF-β1 on noradrenergic neurons is mediated via the TGFβ1R1 receptor, the selective antagonist of this receptor, LY2109761 (0,033 mg/kg), was administered intro the lateral cerebral ventriculi (5μl, in 10 doses, i.c.v.), one hour prior to the electrophysiological recordings... In can be concluded that acute nasal administration of TGF-β1 inhibited noradrenergic neurons of the LC, via a mechanism involving TGFβ1R1. An increase in extracellular noradrenaline levels and activation of..."

Preclinical • CNS Disorders • Depression • TGFB1

GOLPH3 promotes papillary thyroid carcinoma by regulating the TGF-β signaling pathway. (PubMed, Mol Genet Genomics) - "However, as an inhibitor of this pathway, LY2109761 could reverse the effects induced by GOLPH3 overexpression. Collectively, these findings establish GOLPH3 as a critical driver of PTC malignancy through TGF-β pathway activation, providing a mechanistic link between Golgi function and cancer signaling. This work not only advances our understanding of PTC pathogenesis but also identifies GOLPH3 as a potential therapeutic target for aggressive PTC, offering a paradigm for exploring Golgi-associated proteins in endocrine malignancies."

Journal • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • CDH1 • CDH2 • SMAD2 • SMAD3 • SNAI1 • TGFB1

Potent disruption of TGFβ signaling using selective chemical inhibitors or a dominant-negative version of TGFβ receptor type II (ASRI 2026) - "Three selective TGFβ inhibitors (Selleck Chemicals LLC, Houston, TX) were tested at concentrations that straddled the reported 50% effective concentration (EC50): SD208 (50nM); IDT1 (500nM); and LY2109761 (40nM). Future research intends to investigate the ability of SD208 and/or a dnR2 to confer TGFβ resistance to NK cells and potentiate their antitumor efficacy in vitro and in vivo. While intermittent dosing with chemical inhibitors can be used to study temporal aspects of modulating TGFβ signaling, we favor the dominant negative approach as systemic use of TGFβ inhibitors lack specificity and can increase risk of adverse events."

SMAD2 • TGFBR2

FURIN induces vascular endothelial cell death and efferocytosis through enzymatic cleavage of thrombospondin-1. (PubMed, J Physiol) - "Furthermore quantitative RT-PCR assays and western blot analyses showed that FURIN knockdown resulted in a decrease in THBS1 mRNA and protein levels, whereas THBS1 knockdown attenuated FURIN expression, and these reciprocal regulatory effects were augmented in the presence of LY2109761, an inhibitor of transforming growth factor-β receptors...FURIN binds to and cleaves THBS1, thereby promoting endothelial apoptosis and efferocytosis, increasing endothelial permeability and impairing vascular homeostasis. These findings provide new insights into endothelial dysfunction with atherogenic and therapeutic relevance."

Journal • Atherosclerosis • Cardiovascular • FURIN • THBS1

Overcoming PARP inhibitor resistance in triple-negative breast cancer models through olaparib and RAD51 inhibition with TGF-beta 2 downregulation (AACR 2025) - "RAD51 and PARP combinatory inhibition effectively overcomes Olaparib resistance in BRCA1-mutatnt and wild-type TNBC PDX models. RAD51 inhibition decreased expression of TGF-β2 in TNBC tumors, suggesting targeting RAD51 and TGF-β2 may be a potential therapeutic strategy to overcome Olaparib resistance in triple-negative breast cancer."

Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • RAD51 • TGFB1 • TGFB2

All-trans retinoic acid modulates proliferation and apoptosis of secondary hair follicle-dermal papilla cells in cashmere goats via the TGF-β2/Smad2/3 pathway. (PubMed, Front Vet Sci) - "The TGF-β type I/II receptor inhibitor LY2109761 was used to further validate the involvement of this pathway...Overall, ATRA inhibits proliferation and promotes apoptosis in SHF-DPCs, likely through the TGF-β2/Smad2/3 pathway. These findings provide novel insights into ATRA-mediated regulation of hair growth and offer a theoretical basis for future research on cashmere goat SHF development."

IO biomarker • Journal • BAX • BCL2 • TGFB1 • TGFB2

Exploring the mechanism of nonylphenol-induced myocardial fibrosis based on TGF-β1/Smads signaling pathway. (PubMed, Biochem Pharmacol) - "TGF-β receptor type I/II inhibitors (LY2109761) reversed increased levels of NP-induced HYP and partially inhibited the expression of the TGF-β1/Smads signaling pathway and its downstream factors. This study demonstrates that exposure to NP during the pregnancy and lactation periods activates the TGF-β1/Smads signaling pathway and its downstream factors, thereby initiating the development of MF in their offspring. Moreover, the TGF-β1/Smads signaling pathway was determined to be involved in NP-induced CFs fibrosis, highlighting TGF-β1 as a critical target of NP-induced MF."

Journal • Cardiovascular • Fibrosis • Immunology • CTGF • MMP1 • MMP2 • MMP9 • SMAD2 • SMAD7 • TGFB1 • TIMP1

Immunosuppressive-responsive hydrogel for self-regulated drug release and tumor microenvironment reprogramming. (PubMed, J Control Release) - "To address this, an intelligent and injectable thermo-responsive hydrogel delivery system (LY@CNSG) constructed from cyclodextrin nanosponges and poly(N-isopropylacrylamide) was developed, in response to immunosuppressive prostaglandin E2 (PGE2) levels for autonomously controlling the release of LY2109761 (LY, a TGF-β inhibitor) based on competitive host-guest interaction. In triple-negative breast cancer models, photodynamic therapy combined with LY@CNSG significantly inhibited tumor growth and lung metastasis while enhancing antitumor immune activity. Furthermore, by integrating nitric oxide (NO)-responsive fluorescent probes, we created an integrated hydrogel platform, CYNH2-LY@CNSG, for simultaneous immunomodulator delivery and immune signaling molecule monitoring, providing a novel insight for biomarker monitoring and a more precise immunotherapy paradigm."

Biomarker • IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • TGFB1

Single-cell and immune-context integration identifies basement-membrane/metastasis signatures that sharpen bladder-cancer diagnosis and prognosis. (PubMed, Discov Oncol) - "The MBRG-based model effectively predicts BLCA prognosis, integrates mechanisms of basement membrane remodeling, EMT, and immune suppression, and identifies DDR2 and SERPINF1 in CAFs as potential targets for personalized therapy."

IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CAFs • CD8 • DDR2 • HSPG2 • SLIT2 • TMB

Targeting LTBP2 Reveals a Novel Anti-Cardiac Remodeling Mechanism of Finerenone Against Doxorubicin-Induced Cardiotoxicity. (PubMed, Biomolecules) - "The importance of this pathway was supported by the similar anti-fibrotic effects observed with the TGF-β inhibitor LY2109761. However, our findings on the direct binding of Finerenone to LTBP2 are preliminary and require further validation through additional experimental approaches. These results identify LTBP2 as a novel direct target of Finerenone and reveal an additional mechanism underlying its cardioprotective action, suggesting its potential repurposing for the prevention of DIC."

Journal • Cardiovascular • LTBP2 • SMAD3 • TGFB1

Hypoxic Tumor Microenvironment Promotes Hippo Pathway Transcriptional Activity to Enrich Glioma Stem Cells in the Peri-necrotic Niche of Glioblastoma (SNO 2025) - "AKT inhibition with Capivasertib reduced Zyx phosphorylation and Hippo transcription in hypoxia...Blocking TGFBR2 with inhibitor LY2109761 abolished TGF-β1-induced Hippo activation...In vivo, pharmacologic inhibition of YAP/TAZ with Verteporfin or genetic TAZ knockdown in the RCAS/tv-a mouse model reduced tumor burden and prolonged survival. Flow cytometry confirmed decreased CD133+/CD44+ GSCs in TAZ-deficient tumors. These results demonstrate hypoxia and TGF-β1 signaling to activate YAP/TAZ-driven Hippo signaling, promoting GSC maintenance in the peri-necrotic GBM niche."

Biomarker • Tumor microenvironment • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • CCN1 • CD133 • FOXM1 • OLIG2 • SOX2 • TAFAZZIN • TGFB1 • TGFBR2 • YAP1

TET1 regulates self-renewal of porcine skin-derived stem cells through TGF-β signaling pathway. (PubMed, Cell Signal) - "Treating pSDSCs with LY2109761, a TGF-β signaling inhibitor, produced a phenotype similar to TET1 knockdown...Unlike previous studies that primarily emphasized the epigenetic role of TET1, this study reveals its functional link to a signaling pathway. These findings provide a deeper understanding of SDSCs and suggest that targeting the TET1-TGF-β axis may represent a promising approach to enhance the self-renewal capacity of SDSCs."

Journal • Preclinical • SMAD3 • TGFB1

Mitochondrial-targeted photodynamic therapy combined with TGF-β inhibition potentiates anti-PD-1 therapy in pancreatic ductal adenocarcinoma. (PubMed, J Nanobiotechnology) - "To address these challenges, we develop a liposomal nanodrug that co-encapsulates a mitochondrial-targeted photosensitizer (MP) and a TGF-β receptor inhibitor (LY2109761) to synergize PDT with PD-1 checkpoint blockade...In murine PDAC models, this dual-action strategy transforms the immune-cold TME into an immune-inflamed phenotype, sensitizing tumors to PD-1 therapy and leading to pronounced tumor regression and prolonged survival. Our findings present a promising nanodrug-based approach to remodel the fibrotic and immunosuppressive TME of PDAC and enhance immunotherapeutic outcomes."

Journal • Fibrosis • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • TGFB1

Hypoxic Tumor Microenvironment Promotes Hippo Pathway Transcriptional Activity to Enrich Glioma Stem Cells in the Peri-necrotic Niche of Glioblastoma (WFNOS 2025) - "AKT inhibition with Capivasertib reduced Zyx phosphorylation and Hippo transcription in hypoxia...Blocking TGFBR2 with inhibitor LY2109761 abolished TGF-β1-induced Hippo activation...In vivo, pharmacologic inhibition of YAP/TAZ with Verteporfin or genetic TAZ knockdown in the RCAS/tv-a mouse model reduced tumor burden and prolonged survival. Flow cytometry confirmed decreased CD133+/CD44+ GSCs in TAZ-deficient tumors. These results demonstrate hypoxia and TGF-β1 signaling to activate YAP/TAZ-driven Hippo signaling, promoting GSC maintenance in the peri-necrotic GBM niche."

Biomarker • Tumor microenvironment • Brain Cancer • Glioblastoma • Solid Tumor • CCN1 • CD133 • FOXM1 • OLIG2 • SOX2 • TAFAZZIN • TGFB1 • TGFBR2 • YAP1

Transforming Growth Factor Beta 1/SMAD2 Signalling Axis Regulates Leukemia Stem Cell Marker CD123: Implications for Acute Myeloid Leukemia (ASH 2024) - "Finally, looking at AML/MDS patient sample, we were able to show LY2109761 treatment result in striking reduction in IL3Rα and TGFβ1 responsive gene, ID1.Conclusion : In summary, our results highlight the critical role for the TGFβ1/SMAD2/SMAD4 signalling in skewing transcriptional machinery at the regulatory site of IL3Rα gene which prime progenitors toward inflammatory myelopoiesis. Understanding this TGFβ1 regulatory mechanism in upregulating CD123 may provide valuable insights for the future development of LSC-directed therapies, particularly in AML patients."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Inflammation • Leukemia • Myelodysplastic Syndrome • Oncology • CD123 • CD34 • ID1 • IL3RA • SMAD4 • TGFB1 • TGFB2

CD44 knockdown and TGF‑β inhibition modulate cell proliferation and invasion in claudin‑low breast cancer cells. (PubMed, Oncol Rep) - "CD44 was knocked down in claudin‑low breast cancer cell lines (SUM159 and MDA‑MB‑231), and the TGF‑β receptor (TGFBR) inhibitor LY2109761 (LY‑61) was applied for treatment...Although CD44 depletion may increase EMT‑related signaling, invasion was primarily suppressed by TGF‑β blockade, and the combination with CD44 knockdown further enhanced the inhibition of proliferative phenotypes compared with either treatment alone. This dual‑targeting approach warrants further investigation in claudin‑low breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • ANXA5 • CD24 • CD44 • TGFB1

Butein attenuates cardiac fibrosis by mediating TGF-β1/Smad signaling pathway after myocardial infarction. (PubMed, J Mol Histol) - "Butein mitigated MI development by inhibiting cardiac fibrosis and ECM deposition by inactivating the TGF-β1/Smad signaling pathway."

Journal • Cardiovascular • Fibrosis • Immunology • Myocardial Infarction • TGFB1

Esaxerenone inhibits renal macrophage proliferation through MR/TGF-β1 pathway in db/db mice. (PubMed, Life Sci) - "Esaxerenone inhibits renal macrophage proliferation mediated by high glucose-induced activation of MR and downstream TGF-β1 signaling pathways, thereby mitigating inflammatory and fibrotic damage. These findings suggest that MR blockade may directly target macrophage proliferation and inflammation in DKD."

Journal • Preclinical • Diabetes • Diabetic Nephropathy • Fibrosis • Inflammation • Nephrology • Renal Disease • MRC1 • TGFB1

Autocrine TGF-β1 in Periodontal Ligament-Derived Stem Cell Pellets Enhances Periodontal Regeneration in Class II Furcation Defects of Canine Models. (PubMed, Adv Healthc Mater) - "However, LY2109761, an inhibitor of TGF-β receptor I and II, suppressed periodontal tissue regeneration in immunodeficient mice. In the beagle dog with Class II furcation defects, PDLSC-CP regenerated and repaired periodontal bone defects, which is more effective than the control group, the bone substitutes group, and the mixed group (PDLSC-CP and bone substitutes). These findings highlight PDLSC-CP as a promising strategy for periodontal bone defect treatment, where autocrine TGF-β1 stimulates the TGF-β1/Smad pathway to drive periodontal tissue regeneration."

Journal • Preclinical • TGFB1