resatorvid (TAK-242) / Takeda, Akaza Bioscience - LARVOL DELTA

Preclinical evaluation of macrophage reprogramming in treatment of CTCL (ASH 2025) - "Our data suggest that TLR4 inhibition and CD206 activation in the CTCL tumormicroenvironment inhibit tumor growth by inducing a shift from tumor-promoting to tumor-suppressivemacrophages. Therefore, CD206 binding peptide, RP-832c, and small molecule TLR4 inhibitor, TAK-242,present promising therapeutic options in CTCL."

IO biomarker • Preclinical • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • CD86 • MRC1 • TLR4 • TNFA

The Therapeutic Targeting Effect of Toll-Like Receptors and Their Related Signaling Pathways in Cardiomyopathy. (PubMed, Immunol Invest) - "Preclinical investigations demonstrate favorable outcomes from selective pathway modulation, including TLR4 antagonists (such as TAK-242 and eritoran), MyD88 pathway inhibitors, and nucleic-acid-directed TLR9 strategies. Targeting TLR signaling has strong potential to limit inflammation, curb fibrotic remodeling, and preserve cardiac function across diverse cardiomyopathies. The most promising therapeutic direction involves developing subtype-specific and cell- or pathway-targeted interventions, supported by translational research to bridge preclinical findings with clinical application."

IO biomarker • Journal • Review • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Fibrosis • Genetic Disorders • Heart Failure • Immunology • Inflammation • Obesity • MYD88 • TLR2 • TLR3 • TLR4 • TLR7 • TLR9

Autophagy-dependent secretion of ENO1 mediates chemoresistance of glioblastoma and tumor microenvironment remodeling. (PubMed, Cell Death Dis) - "In this study, we demonstrated that temozolomide (TMZ) could activate the autophagy-dependent secretory pathway to promote extracellular secretion of Alpha-enolase (ENO1)...Importantly, in vivo studies confirmed that combined therapy with the SPHK1 inhibitor PF-543, the TLR4 antagonist TAK-242, and TMZ synergistically suppressed tumor growth and significantly enhanced the efficacy of TMZ. Collectively, these findings reveal that ENO1 mediates intercellular crosstalk between GBM cells and M2-TAMs via autophagy-dependent secretion, thereby driving TMZ chemoresistance and functioning as an oncogene in GBM. Targeting the ENO1/TLR4 signaling axis reshapes the immune microenvironment and enhances the efficacy of TMZ, offering a promising therapeutic strategy and potential combinatorial targets for precision therapy in GBM."

Biomarker • IO biomarker • Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • ENO1 • SPHK1

Toll-like receptor 4 inhibition sensitizes non-small cell lung cancer to radiotherapy. (PubMed, Cancer Biol Ther) - "In vivo, the combination of RT and TAK242 significantly reduced growth of KLN205 tumors. These findings show that TLR4 inhibition enhances RT sensitivity in NSCLC."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HMGB1 • MYD88 • TLR4

A Novel Sesquiterpene from Callistephus chinensis Improves Alcohol-Induced Liver Disease by Regulating the AMPK/NF-κB Signaling Pathway and Gut Flora. (PubMed, Molecules) - "In vitro, by adding inhibitors of TLR4 (TAK-242) and AMPK (Dorsomorphin), it was confirmed that CA alleviates ALD by inhibiting TLR4 and activating AMPK. This study is the first to demonstrate that CA protects against alcoholic liver disease through the regulation of the gut flora and modulation of the AMPK/NF-κB pathway. In conclusion, CA can effectively improve alcoholic liver disease and can be used as an effective candidate drug with liver-protective effects."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • MYD88 • TLR4

Topoisomerase IIα orchestrates secretion of IL-6 and IL-8 with human papillomavirus replication. (PubMed, Virol Sin) - "Blockade of TLR4 signaling by the specific inhibitor TAK-242 significantly reduces the secreted IL-6/IL-8 levels and HPV replication. Overall, our results reveal a novel role of Top2α to shape the inflammatory microenvironment that benefits HPV replication, making it a promising therapeutic target for HPV-associated diseases."

IO biomarker • Journal • Oncology • CXCL8 • IL6 • TOP2A

TLR-2/4 inhibition accelerates bone repair via modulating MyD88/NF-κB signaling and inflammatory microenvironment. (PubMed, Biochem Biophys Res Commun) - "Fracture models were established in Sprague-Dawley (SD) rats and intervened with the TLR-2 inhibitor C29 or the TLR-4 inhibitor TAK-242...These time-dependent effects significantly accelerated late-phase (>14d) fracture repair versus early stages (0-14d), improving bone healing parameters. Targeting TLR-2/4 accelerates fracture repair by suppressing MyD88/NF-κB-driven inflammation and optimizing the bone healing microenvironment."

IO biomarker • Journal • Inflammation • Musculoskeletal Diseases • Oncology • Orthopedics • CTNNB1 • IL6 • MYD88 • RUNX2 • TLR2 • TLR4 • TNFA

Dexmedetomidine Regulates HMGB1 Transferred by HK-2 Cell-Derived Exosomes to Suppress Myocardial Cell Pyroptosis by Activating the TLR4 Signaling Pathway. (PubMed, Ann Clin Lab Sci) - "Dex can significantly inhibit the expression of HMGB1 in HK-2 cell-derived exosomes exposed to H/R and inhibit AC16 cell pyroptosis through exosome uptake and the effect of HMGB1 on the TLR4 signaling pathway."

Journal • Cardiovascular • Reperfusion Injury • HMGB1

Monocyte-Driven Aberrant Inflammation in Myeloproliferative Neoplasms Is Regulated By Galectin-1 (ASH 2024) - "Additionally, Gal-1 expression was induced by MPLW515L and JAK2V617F and inhibited by ruxolitinib, a JAK inhibitor, in Ba/F3 cells...Pharmacologic inhibition of Gal-1 by OTX008 suppressed the expression and secretion of inflammatory cytokines in MPN monocytes and monocytic cell lines...Notably, targeting TLR4 via both neutralizing antibody and pharmacologic inhibition (TAK-242) abrogated the proinflammatory effects of Gal-1 on monocytes...We further evaluated therapeutic effects of targeting global glycosylation in MPN via 2-Deoxy-D-glucose (2-DG), a global glycosylation inhibitor, which decreased splenomegaly and reduced elevated platelets and hematocrit in JAK2V617F knock-in mice...We further demonstrate that Gal-1 fuels monocyte inflammation by interacting with TLR4 and activation of OXPHOS and PI3K-AKT-mTOR signaling pathways. Our results uncover a novel therapeutic avenue for targeting aberrant Gal-1 and global glycosylation in MPNs."

Cardiovascular • Myeloproliferative Neoplasm • Oncology • Thrombosis • CD14 • CXCL8 • IL1B • IL6 • ITGAM • LGALS1 • TLR4

S100A4 Induces Neutrophilic Inflammation in Chronic Rhinosinusitis with Nasal Polyps via TLR4 Pathway. (PubMed, J Clin Immunol) - "S100A4 is elevated in neutrophilic CRSwNP and exerts its pro-inflammatory effect on nasal epithelial cells via TLR4 signaling cascade."

Journal • Chronic Rhinosinusitis With Nasal Polyps • Fibrosis • Immunology • Inflammation • Nasal Polyps • Otorhinolaryngology • Respiratory Diseases • Sinusitis • S100A4

TLR4 Inhibition Attenuate Facilitatory Effects of JQ1 on Learning & Memory Via Polarization of Microglia, and BDNF Expression in Alzheimer's Disease Model. (PubMed, Behav Brain Res) - "Our results indicate that JQ1 successfully improves learning and memory in the rat model of Alzheimer's disease, primarily by inducing the transcription of BDNF expression and suppressing inflammatory factors related to the M1 microglia. In contrast, co-treatment with a TLR4 inhibitor attenuate both spatial and aversive memories, probably through a decrease in BDNF expression."

IO biomarker • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • BDNF • BRD4 • TLR4

10-hydroxydec-2-enoic acid alleviates post-myocardial infarction inflammation and oxidative stress by modulating the TLR4 signaling axis. (PubMed, Phytomedicine) - "10-HDA protects against MI-induced cardiac injury by inhibiting TLR4/MyD88/ NF-κB pathway to reduce myocardial inflammation and oxidative stress."

Journal • Cardiovascular • Fibrosis • Immunology • Inflammation • Myocardial Infarction • MYD88 • NFKBIA • TLR4

Investigating the Effects of Gardenia Polysaccharides on LPS-Induced Immune Injury in Mice and Exploring the Molecular Mechanisms Underlying Its Regulatory Effect on the Immune Function of Macrophages. (PubMed, Foods) - "These effects were observed in cells not pretreated with TAK-242 or PDTC; however, they were not observed in cells pretreated with these inhibitors...Collectively, these findings indicated that GP reversed systemic immunosuppression and oxidative stress, offering foundational insights for developing natural immune regulators. The observed immunomodulatory properties of GP are likely mediated through the TLR4/NF-κB signaling pathway."

Journal • Preclinical • Immunology • IL1B • IL6 • MYD88 • TLR4 • TNFA • TRAF6

TAK-242 inhibits toll-like receptor-4 signaling and attenuates cancer-associated muscle atrophy via the p38-C/EBPβ pathway. (PubMed, J Mol Histol) - "TLR4 plays a critical role in cancer-associated muscle atrophy through the p38β MAPK-C/EBPβ signaling pathway in both in vitro and in vivo models. Pharmacological inhibition of TLR4 with TAK-242 effectively attenuated muscle atrophy, highlighting its potential therapeutic value."

IO biomarker • Journal • Cachexia • Muscular Atrophy • Oncology • FBXO32 • TLR4

Animal experiment on osseointegration of porous titanium root analogue implants with composite CSn-TAK242 coating. (PubMed, Front Bioeng Biotechnol) - "Porous titanium root analogue implants consistent with the target root morphology were successfully fabricated using digital medical technology and 3D printing. The composite CSn-TAK242 coating further enhanced the osseointegration effects of these implants."

Journal • TLR4

The EZH2 Inhibitor GSK126 Alleviates Thromboinflammation in Deep Vein Thrombosis by Suppressing TLR4 Signaling via H3K27me3 Modulation. (PubMed, J Inflamm Res) - "In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated with lipopolysaccharide (LPS) and treated with GSK126, either alone or in combination with the TLR4-specific inhibitor TAK-242. These findings suggest that GSK126 alleviates TLR4-mediated inflammation, likely through its modulation of histone methylation, specifically H3K27me3. Our results support a role for TLR4 signaling in DVT pathogenesis and suggest that EZH2 inhibition with GSK126 may represent a novel therapeutic approach to thromboinflammation by modulating H3K27me3 and suppressing TLR4-driven inflammatory pathways."

IO biomarker • Journal • Cardiovascular • Hematological Disorders • Inflammation • Thrombosis • Venous Thromboembolism • NFKBIA

Asiaticoside Alleviates Migraine-Induced Cognitive Impairment via TLR4-Mediated Apoptosis Regulation. (PubMed, Eur J Pharmacol) - "In vivo validation was conducted using a nitroglycerin (NTG)-induced migraine mouse model, incorporating behavioral assessments alongside biochemical and molecular analyses. Co-administration of the TLR4 inhibitor TAK-242 further enhanced Asiaticoside's protective effects. These findings collectively support that Asiaticoside alleviates migraine-induced cognitive impairments by modulating TLR4-mediated neuroinflammation and apoptosis, highlighting its promise as a potential therapeutic agent for migraine and its associated cognitive impairment."

IO biomarker • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Immunology • Inflammation • Migraine • Pain • BCL2 • CASP3 • MYD88 • TLR4

Gut microbiota dysbiosis promotes coronary heart disease comorbid with depression through lipopolysaccharides and Toll-like receptor 4. (PubMed, BMC Microbiol) - "The TLR4 inhibitor TAK-242 was administered, creating the Disease + TAK-242 and FMT-Disease-TAK-242 groups...Additionally, after receiving fecal microbiota from healthy rats, the Disease group showed a restoration of gut microbiota balance, improvement in general condition, and normalization of pathological, biochemical, and inflammatory indicators, indicating a suppressive effect on the progression of CHD with depression.  Our findings further clarify the interrelationship between gut microbiota and CHD comorbid with depression, enhancing our understanding of its pathogenesis. Moreover, we propose a potential novel therapeutic strategy that focuses on modulating gut microbiota composition to block the TLR4/MYD88/NF-κB inflammatory pathway."

IO biomarker • Journal • Cardiovascular • CNS Disorders • Coronary Artery Disease • Depression • Heart Failure • Mood Disorders • Psychiatry • Transplantation • MYD88 • TLR4

Structure-function insights into galactans of Endocladia muricata: Physicochemical properties and immunomodulatory activity. (PubMed, Carbohydr Polym) - "Immunological assays showed that the saline-alcohol precipitated EM-2B fraction strongly activated RAW264.7 macrophages, increasing iNOS and COX-2 expression, NO/ROS production, and pro-inflammatory cytokine release via TLR4 signaling, as shown by TAK-242 inhibition...These results underscore the immunomodulatory potential of E. muricata galactans, with sulfation, methoxylation, and domain architecture playing key roles. Their block-wise structural organization and gelling properties highlight their promise as biofunctional hydrocolloids for food and biomedical applications."

Journal • Immunology • PTGS2

Resatorvid as a Promising Neuroprotective Agent in Pentylenetetrazol-Kindling Rat Model: Suppressing Neuroinflammation and Enhancing Cognitive and Motor Functions. (PubMed, Eur J Pharmacol) - "This study investigated the neuroprotective effects of resatorvid (0.25 mg/kg) in a pentylenetetrazole (PTZ)-induced kindling model in rats. Seizures were induced by PTZ (35 mg/kg, every other day, i.p), and once full kindling was established, animals received either resatorvid or the standard antiepileptic drug carbamazepine for 14 days...These findings suggest that resatorvid exerts a multimodal neuroprotective effect by attenuating neuroinflammation and glial reactivity, preserving hippocampal structure, and improving cognitive and motor functions. Altogether, the results highlight resatorvid as a promising therapeutic candidate for epilepsy, warranting further exploration in preclinical and clinical settings."

IO biomarker • Journal • Preclinical • CNS Disorders • Epilepsy • Inflammation • CXCL8 • GFAP • HMGB1 • TLR4

Real-time monitoring with iTLR4 assay identifies ligand-dependent TLR4-TLR4 conformational dynamics. (PubMed, Front Immunol) - "While all antagonists completely abolished LPS-induced IL-8 secretion, the assay demonstrated that at the receptor level LPS-RS completely inhibited the LPS-induced BRET signal, TAK-242 partially inhibited it and (+)-naloxone potentiated it...These findings highlight the unique capabilities of the iTLR4 assay to track nuanced TLR4 receptor dynamics, enabling high-throughput screening of TLR4-specific modulators. This platform provides critical insights into ligand-induced signaling, paving the way for the development of novel therapeutics targeting TLR4-related diseases and advancing our understanding of innate immune responses."

IO biomarker • Journal • CD14 • CXCL8 • TLR4

Sleep deprivation disrupts vestibular compensation by activating TLR4/NF-κB/NLRP3 signalling in the deafferented vestibular nuclei. (PubMed, Brain Res Bull) - "Minocycline and TAK-242 were used to inhibit microglial activation and TLR4, respectively. Mechanistically, TLR4/NF-κB/NLRP3 pathway activation was predominantly involved in this process, and pharmacological inhibition of TLR4 inhibited NLRP3 activation in microglia and improved SD-induced vestibular compensation delay. Overall, this study illustrates that SD alters neuroplasticity and aggravates microglia-mediated neuroinflammation in deafferented VN by activating TLR4/NF-κB/NLRP3 signalling, which contributes to impaired vestibular compensation."

Journal • Inflammation • NLRP3 • TLR4

20(R)-ginsenoside Rg3 Inhibits Neuroinflammation Induced by Cerebral Ischemia/Reperfusion Injury by Regulating the Toll-Like Receptor 4/Myeloid Differentiation Factor-88/Nuclear Factor Kappa B Signaling Pathway. (PubMed, Chem Biodivers) - "In addition, 20(R)-Rg3 enhanced the anti-inflammatory efficacy of the TLR4 inhibitor TAK-242 and reduced inflammation in OGD/R-exposed neurons. 20(R)-Rg3 attenuates neuroinflammation and protects neurons via inhibiting TLR4/MyD88/NF-κB pathway in vitro and in vivo, suggesting it is a potential therapeutic for ischemic stroke."

IO biomarker • Journal • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke • Reperfusion Injury • MYD88 • TLR4

The antitumor effect of tlr4 inhibition in head and neck cancer cell lines. (PubMed, Sci Rep) - "In combination with cisplatin, TAK242 demonstrated an additive effect, increased cisplatin sensitivity in SCC154, and altered the death mechanism induced by cisplatin in SCC78 cells. In conclusion, TLR4 inhibition led to antitumor effects independent of HPV infection status or TP53 status, suggesting that TLR4 may be a broad-spectrum target for HNC therapy."

IO biomarker • Journal • Preclinical • Head and Neck Cancer • Human Papillomavirus Infection • Infectious Disease • Oncology • Solid Tumor • IL6 • TLR4

Mechanisms of Pain Hypersensitivity in a Human Skin Inflammation Model (clinicaltrials.gov) - P1 | N=42 | Completed | Sponsor: Stefan Heber

New P1 trial • Dermatitis • Immunology • Inflammation • Pain