JNK-IN-8 / Dana-Farber Cancer Institute, University of North Carolina-Chapel Hill - LARVOL DELTA

JNK1 and JNK2 isoforms promote triple-negative breast cancer aggressiveness by fostering an M2 macrophage-driven immunosuppressive tumor microenvironment (SABCS 2025) - "However, the distinct roles of JNK1 and JNK2 inregulating the TME immune landscape and aggressiveness in TNBC remain poorly understood.Building on our previous findings, in this study, we tested our hypothesis that both JNK1 andJNK2 promote TNBC aggressiveness by fostering an M2 macrophage–drivenimmunosuppressive TME. The effect of JNK singling inhibition by the pan-JNK inhibitor JNK-IN-8 and theeffect of JNK1 or JNK2 knockout (KO) on the growth of murine PyMT-M TNBC cells wereassessed in vitro using CellTiter-Blue cell viability and clonogenic assays... Our findings demonstrate that both JNK1 and JNK2 in the TME drive TNBCinitiation and progression via promoting an M2 macrophage–driven immunosuppressive TMEin the macrophage-enriched TNBC mouse model. These findings establish JNK1 and JNK2 askey regulators of the immunosuppressive TME in TNBC, highlighting their therapeuticimportance in treating TNBC."

Biomarker • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CCL2 • CXCL9 • MAPK8 • MAPK9

Targeting Pro-Metastatic Stress Kinase Networks in Triple-Negative Breast Cancer Using Patient-Derived Models (SABCS 2025) - " We show that combinations of 3 kinase inhibitors used in early phase clinical trials (Ralimetinib (p38), JNK-in-8 (JNK) or FDA approved (Trametinib (MEK & ERK1/2)) inhibit stress kinase networks, pro-motility gene expression and TNBC cell invasion. Inhibition of these stress kinase networks should enable effective reprogramming of metastatic or high-risk cancers to more benign states and make tumors more susceptible to approved anti-proliferative therapies such as chemotherapy or immunotherapy while limiting toxicities from kinase inhibitors using a low-dose, multi-drug combination approach."

Clinical • IO biomarker • Metastases • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BACH1 • BRIP1 • PEBP1

CEACAM7 enhances oral cancer metastasis by upregulating CD317 expression. (PubMed, Life Sci) - "These findings suggest that CEACAM7 promotes oral cancer metastasis by regulating CD317 through the p-JNK and p-Src pathways. CEACAM7 and CD317 may therefore represent potential therapeutic targets for the treatment of metastatic oral cancer."

Journal • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • BST2 • CEACAM5

Inhibiting JNK and PI3K-Akt signaling pathways altered spontaneous network bursts and developmental trajectories of neuronal networks. (PubMed, J Neural Eng) - "This study investigates the roles of JNK and PI3K-Akt signaling in regulating spontaneous NBs dynamics and network organization in cultured neuronal networks. Approach: Using longitudinal microelectrode array (MEA) recordings from cultured cortical neurons (DIV14-49), we pharmacologically inhibited JNK (SP600125, JNK-IN-8) and PI3K-Akt (LY294002, GDC-0941) pathways. JNK signaling is crucial for maintaining early core-node functionality, whereas PI3K-Akt signaling promotes the development of mature modular architecture. Our findings enhance the understanding of how molecular signaling influences neuronal network dynamics, contributing to a broader framework for studying neurodevelopmental principles.&#xD."

Journal

The Role of c‑Jun Signaling in Cytidine Analog-Induced Cell Death in Melanoma. (PubMed, ACS Omega) - "Enhanced mitochondrial metabolism has been reported in melanoma cells that survived treatment with traditional therapeutics, including cytidine analogs like gemcitabine (GEM)...Co-treatment with a Jun N-terminal Kinase (JNK) inhibitor, JNK-IN-8 (JNKi), significantly increased cell survival, suggesting the involvement of c-Jun signaling in GEM-induced cell death. Additionally, proteomics analysis revealed that JNKi downregulated apoptosis in cotreated cells, highlighting the potential role of the JNK/c-Jun network inhibition in chemotherapeutic tolerance. Collectively, our findings bridge gaps in understanding how melanoma cells respond to cytidine analogs by demonstrating the multifaceted effects of these agents in (1) inducing JNK-mediated apoptotic cell death and (2) promoting a state of cell cycle inhibition."

Journal • Melanoma • Oncology • Solid Tumor

Macranthoside B Enhances Paclitaxel-induced Human Cervical Cancer Cell Apoptosis Through ROS-JNK Pathway. (PubMed, Anticancer Res) - "MB increases PTX-mediated HeLa cell apoptosis by overgeneration of ROS and activating MAPKs/JNK pathway."

Journal • Cervical Adenocarcinoma • Cervical Cancer • Oncology • Solid Tumor

Matrix stiffness-induced IKBKE and MAPK8 signaling drives a phenotypic switch from DCIS to invasive breast cancer. (PubMed, Cell Commun Signal) - "The IKBKE-inhibitor Amlexanox, clinically utilized for aphthous ulcers, as well as the MAPK8 inhibitor JNK-IN-8, reinstalled the DCIS-like phenotype of breast cancer cells on high matrix stiffness. This suggests that IKBKE and/or MAPK8 inhibitors could enhance the arsenal of treatments to prevent or treat breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • IKBKE • MAPK8

Jun N-Terminal Kinase Inhibitor Suppresses CASK Deficiency-Induced Cerebellar Granular Cell Death in MICPCH Syndrome Model Mice. (PubMed, Cells) - "Moreover, injection of JNK-IN-8 into the cerebellum of CASK+/- HprteGFP/+ mice suppressed CG cell death and alleviated cerebellar ataxic phenotypes in vivo. In conclusion, JNK-IN-8 suppresses the cell death and activation of the ROS pathway in CASK-KO CG cells in both in vitro and in vivo models, suggesting its potential as a therapeutic strategy for cerebellar neurodegeneration in MICPCH syndrome."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Psychiatry • CLSPN,

JNK PATHWAY MODULATES THE SA-1 REGULATION OF PD-L1: IMPLICATIONS FOR COLORECTAL CANCER (CRC) IMMUNOTHERAPY (DDW 2025) - "Finally, to ascertain the importance of JNK, we used a standard JNK Inhibitor, JNK-IN-8...On the other hand, JNK inducers might provide the drive to upregulate PD-L1 and thereby render the tumor susceptible to checkpoint inhibitors. One could consider SA-1 and JNK activation status may be surrogate biomarkers for checkpoint inhibitor responsiveness and thus may have real clinical applications in the future."

IO biomarker • Colorectal Cancer • Oncology • Solid Tumor • ANXA5 • CD2 • GAPDH • NCAM1 • PD-L1

Targeting pro-metastatic stress networks in triple-negative breast cancer using patient-derived models (AACR 2025) - "We show that combinations of kinase inhibitors used in early phase clinical trials (Ralimetinib (p38), JNK-in-8 (JNK) or FDA approved (Trametinib (MEK & ERK1/2)) can inhibit stress kinase networks, pro-motility gene expression and TNBC cell migration. We utilized mass spectrometry-based techniques with a kinase inhibitor system (MIB-MS) and proteomics to characterize the activation state of kinase signaling networks in organoids and are investigating the effect of metastatic inhibitors on these pathways. Inhibition of these stress kinase networks should enable effective reprogramming of metastatic or high-risk cancers to more benign states and make tumors more susceptible to approved anti-proliferative therapies such as chemotherapy or immunotherapy while limiting toxicities from kinase inhibitors using a low-dose, multi-drug combination approach."

Clinical • IO biomarker • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BACH1 • BRIP1 • HER-2 • PEBP1

Triethylene-glycol-dimethacrylate induces caspase-mediated apoptotic cell death in cementoblasts by the regulation of JNK and p38 pathways-an in vitro study. (PubMed, J Dent Sci) - "In addition, both c-Jun N-terminal kinase (JNK) inhibitor JNK-in-8 and p38 inhibitor SB203580 dramatically reduced TEGDMA-induced caspase 8, 9, and 3 activations in OCCM.30 cells, respectively (P < 0.05). Taken together, our results demonstrated that TEDGMA decreased cell viability and induced the apoptotic cell death in cementoblast. In addition, caspase-mediated cell apoptosis was found to be associated with JNK and p38 signal transduction pathways."

Journal • Preclinical • CASP8 • CASP9 • MAPK8

C6TSEDRVAJZ, a combination of small-molecule compounds, induces differentiation of human placental fibroblasts into epithelioid cells in vitro (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "The small-molecule compound combination C6TSEDRVAJZ is capable of inducing HPFs into ciEP-Ls under hypoxic conditions with a high induction efficiency."

Journal • Preclinical • CD34 • CDH1 • COL1A1 • GLI3 • KRT18 • KRT18 • KRT19 • PAX8 • S100A4 • SMAD3 • VIM • WT1

Curcumin Analog GO-Y030 Triggers JNK and p38 Signalling to Activate Apoptotic Cascades in Human Osteosarcoma Cells. (PubMed, J Cell Mol Med) - "Inhibitors of JNK (JNK-IN-8) and p38 (SB203580) suppressed GO-Y030-induced cleavage of caspases 8, 9, and 3, whereas co-treatment with the ERK inhibitor (U0126) did not lessen their activation. Overall, GO-Y030 triggers both extrinsic and intrinsic apoptotic cascades in U2OS and 143B cells by activating the JNK1/2 and p38 pathways, shedding light on its mechanism of action against human osteosarcoma cells."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • ANXA5 • CASP8 • CASP9 • MAPK8

Transient Receptor Potential Ankyrin 1 (TRPA1) Mediated LPS-Induced Inflammation in Periodontal Ligament Stem Cells by Inhibiting the Phosphorylation of JNK. (PubMed, Stem Cells Int) - "The use of JNK inhibitor JNK-IN-8 can also reduce the expression of IL-1β, IL-6, and IL-8 in PDLSCs. Finally, this study found LPS could cause the upregulation of TRPA1, and the inhibition of TRPA1 could produce an anti-inflammatory effect in PDLSCs treated by LPS due to its inhibition of JNK phosphorylation."

Journal • Asthma • Cardiovascular • Cough • Diabetes • Genetic Disorders • Immunology • Inflammation • Metabolic Disorders • Nephrology • Obesity • Osteoarthritis • Pain • Pulmonary Disease • Renal Disease • Respiratory Diseases • Rheumatology • CXCL8 • IL1B • IL6 • TRPA1

Inhibition of JNK signaling attenuates photoreceptor ferroptosis caused by all-trans-retinal. (PubMed, Free Radic Biol Med) - "Importantly, intraperitoneal administration of JNK-IN-8 significantly rescued retinal function and photoreceptors from ferritinophagy-induced ferroptosis and effectively mitigated retinal degeneration in light-exposed Abca4-/-Rdh8-/- mice. This study underscores the critical role of the JNK/c-Jun/NCOA4 axis in mediating atRAL-induced ferritinophagy, which drives ferroptosis and retinal atrophy, suggesting that targeting this pathway may offer a potential therapeutic approach for STGD1 and dry AMD."

Journal • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Hematological Disorders • Inherited Retinal Dystrophy • Macular Degeneration • Ophthalmology • Retinal Disorders • MAPK8 • MAPK9 • NCOA4

Inhibiting JNK signaling enhances the antitumor efficacy of macrophage-targeting agents in triple-negative breast cancer by inducing an immunoactive tumor microenvironment (SABCS 2024) - P1 | "Indeed, JNK inhibitor (JNKi) BMS-986360 is currently being tested alone and in combination with chemotherapy or nivolumab in advanced solid tumors (NCT05625412)...The antitumor efficacy of JNKi (BMS-986360, a reversible orally active pan-JNKi; or JNK-IN-8, a covalent pan-JNKi) combined with macrophage-targeting agents (pexidartinib or sotuletinib, both of which are orally active CSF-1R inhibitors) was assessed using immunocompetent syngeneic models of E0771 (M1 macrophage-enriched TME, sensitive to immune checkpoint inhibitors [ICI]), PyMT-M (M2-macrophage-enriched TME, partially sensitive to ICI), and 4T1.2 (neutrophil-enriched TME, resistant to ICI)... JNKi can potentiate macrophage-targeting agents in TNBC by inducing an immunoactive TME. This finding highlights the need to conduct further studies of combining JNKi with immunotherapy to capitalize on JNK's immune regulation of the TME and the potency of JNKi in synergistically improving the efficacy of..."

Biomarker • Clinical • IO biomarker • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CCL2 • CD8 • MAPK8 • TGFB1

JNK MAPK Inhibition Reprograms Stromal Inflammation and the Immunosuppressive Tumor Microenvironment to Enhance Chemosensitivity in PDAC (ACS-CLINCON 2024) - " Inhibition of JNK was achieved pharmacologically with JNK-IN-8 (JNKi) in human and murine PDAC tumor and CAF cell lines... These findings provide preclinical evidence that JNK inhibition overcomes chemo- and immunotherapy resistance by reprogramming stromal inflammation and the immunosuppressive PDAC TME and enhances current treatment strategies in PDAC."

Biomarker • IO biomarker • Stroma • Tumor microenvironment • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD8 • KRAS • TGFBR2

Exploring the Combined Effects of Tamoxifen and Radiotherapy, Regardless of Estrogen Receptor Status (ASTRO 2024) - "After depleting TAMs with clodronate liposomes, the synergistic effect of RT with tamoxifen vanished...The addition of JNK-IN-8, an inhibitor of JNK, supports the pivotal role of the JNK/c-Jun pathway in the process of M1 polarization induced by tamoxifen combined with RT. All in all, we found RT combined with high-dose tamoxifen could significantly activate the JNK/c-Jun pathway, and then modulate the immune microenvironment, finally resulting in a stronger antitumor effect in vivo. The immunomodulatory function may open a new chapter for the application of tamoxifen."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CD8 • CD86 • ER • GZMB • MRC1 • TNFA

Microdosing Partial Agonists Inactivates Kappa Opioid Receptors - An Alternative Strategy for Human Trials (CPDD 2024) - "KOR-mediated analgesia, aversion, fentanyl withdrawal, prolactin release, diuresis, and antipruritic effects were assessed (n = 6-16)...This response was blocked by naloxone (opioid antagonist), JNK-IN-8 (JNK inhibitor), or MJ33 (PRDX6 inhibitor)... These findings suggest that chronic low-dose treatment with nalfurafine or nalmefene could offer a safer, more targeted approach to KOR inactivation, with fewer side effects compared to competitive KOR antagonists. The observed tissue-specific effects, with no interference in diuretic or antipruritic responses, indicate tissue-specific selectivity. The lower doses required for KOR inactivation may minimize off-target adverse effects, making them attractive candidates for prolonged use and highlighting their potential to promote stress resilience with therapeutic selectivity."

Addiction (Opioid and Alcohol) • CNS Disorders • Cognitive Disorders • Mood Disorders • Psychiatry • Tobacco Addiction • PRDX6

JNK inhibition reprograms the tumor-immune-microenvironment to overcome chemoresistance in PDAC (SSO 2024) - "An orthotopic mouse model of PDAC was treated with vehicle, JNK-IN-8 (20mg/kg, daily IP), gemcitabine and paclitaxel (g-p) or the combination of gem-pac and JNK-IN-8 for 4 weeks and tumors harvested for downstream analysis. These findings provide compelling evidence to explore JNKi as a novel treatment strategy to overcome therapeutic resistance through modulation of the stromal and immune microenvironment in PDAC. We further show potential for combining immune checkpoint inhibition therapy with chemotherapy plus JNKi to further enhance therapeutic efficacy. Learning Objectives: Describe the changes seen within the tumor microenvironment of PDAC and the inherent challenges this poses to effective therapy of this disease which leads to poor clinical outcomes for patients."

IO biomarker • Oncology • CD8 • IL6 • KRAS • MAPK8 • TNFA

Targeting c-Jun is a potential therapy for luminal breast cancer bone metastasis. (PubMed, Mol Cancer Res) - "Pharmacological inhibition of c-Jun by the Jun amino-terminal kinase (JNK) inhibitor JNK-IN-8 effectively suppressed tumorigenesis and bone metastasis in MCF7-BM cells...Our results illustrate the potential benefits of a therapy that targets c-Jun to prevent bone metastasis in luminal breast cancer. Implications: c-Jun expression mediates bone metastasis in luminal breast cancer by forming a vicious cycle in the bone microenvironment, which reveals potential strategies for subtype-specific bone metastasis therapy."

Journal • Breast Cancer • Oncology • Solid Tumor • JUN

Apoptotic effect and cell arrest of deoxyshikonin in human osteosarcoma cells through the p38 pathway. (PubMed, J Cell Mol Med) - "Subsequently, cotreatment with inhibitors of ERK (U0126), JNK (JNK-IN-8) and p38 (SB203580) was performed to show that p38 signalling is responsible for deoxyshikonin-induced apoptosis in U2OS and HOS cells, but not via the ERK and JNK pathways. These discoveries demonstrate that deoxyshikonin may be a possible chemotherapeutic candidate to induce cell arrest and apoptosis by activating extrinsic and intrinsic pathways through p38 for human osteosarcoma."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CASP3 • CASP8 • CASP9 • MAPK8 • XIAP

JNK-IN-8 treatment improves ARDS-induced cognitive impairment by inhibiting JNK/NF-κB-mediated NLRP3 inflammasome. (PubMed, Brain Behav) - "Our data suggest that JNK-IN-8 treatment improves ARDS-induced cognitive impairment by inhibiting the JNK/nuclear factor-κB-mediated NLRP3 inflammasome."

Journal • Acute Respiratory Distress Syndrome • Alzheimer's Disease • Cognitive Disorders • Inflammation • Pulmonary Disease • Respiratory Diseases • MAPK8 • NF-κβ • NLRP3

Identification of Kinase Targets for Enhancing the Antitumor Activity of Eribulin in Triple-Negative Breast Cell Lines. (PubMed, Biomedicines) - "Our data suggest a new strategy of combining eribulin with PI3K or mTOR inhibitors to treat TNBC."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Inhibition of mGluR5 ameliorates lipid accumulation and inflammation in HepG2 cells. (PubMed, Biochem Biophys Res Commun) - "Inhibition of JNK signaling by JNK-IN-8 rescued CHPG-induced lipogenesis and inflammation. This study showed mGluR5 regulated lipid accumulation and inflammation in palmitic acid-treated HepG2 cells via the JNK signaling pathway. mGluR5 might be a potential drug target for NAFLD."

Journal • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • NF-κβ • RELA