SP600125 / BMS - LARVOL DELTA

MST1 modulates inflammation by inhibiting BNIP3 -dependent mitophagy via the JNK/p53 pathway in acute lung injury. (PubMed, Tissue Cell) - "The JNK/p53/BNIP3 pathway was examined using Western blot, qRT-PCR, immunofluorescence, and interventions with siRNA-p53 and the JNK inhibitor SP600125...In summary, MST1 suppresses BNIP3 via the JNK/p53 pathway, thereby promoting inflammation and impairing mitophagy in LPS-induced injury. These findings not only identify MST1 as a potential therapeutic target for ALI but also elucidate a novel mechanism regulating mitochondrial homeostasis during inflammation."

Journal • Acute Lung Injury • Inflammation • Metabolic Disorders • Respiratory Diseases • MST1 • SLK

PACS2 deficiency ameliorates hepatic steatosis via inhibition of the JNK signaling pathway in diabetic mice. (PubMed, Biochem Pharmacol) - "HepG2 cells treated with siRNA-PACS2 or SP600125 resulted in the inhibition of HGPA-mediated enhancement of JNK activation and the lipogenic enzymes expression (acetyl-CoA carboxylase 1 and fatty acid synthase), as well as the promotion of PPARα and fatty acid β-oxidation (FAO)-associated CPT1A expression. Collectively, our findings demonstrate that PACS2 deficiency alleviates hepatic steatosis and insulin resistance in diabetic mice by inhibition of JNK signaling pathway in hepatocytes."

Journal • Preclinical • Diabetes • Metabolic Disorders • ACACA • CPT1A • FASN • PPARA

Wnt-3a exacerbates production of TNF-α in LPS stimulated microglia independent of the β-catenin canonical pathway. (PubMed, Sci Rep) - "Canonical pathway inhibition via DKK1 showed no changes in TNF-α levels, however both SP600125 and U723122 were able to block Wnt-3a + LPS induced TNF-α release, implicating non-canonical pathways...Together, these findings suggest Wnt-3a may enhance pro-inflammatory TNF-α release via non-canonical signaling in inflammatory conditions, with minimal effect on homeostatic microglia. This demonstrates the importance of cellular context when identifying potential therapies for neurodegenerative diseases where neuroinflammation is a critical mediator of pathology."

Journal • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • DKK1 • IL1B • TNFA

Methyl Protodioscin Promotes Ferroptosis of Prostate Cancer Cells by Facilitating Dissociation of RB1CC1 from the Detergent-Resistant Membranes and Its Nuclear Translocation. (PubMed, Biomolecules) - "As the nuclear translocation of RB1CC1 was promoted by the JNK signaling pathway, SP600125, a JNK inhibitor, prevented the MPD-induced RB1CC1 nuclear translocation. In summary, MPD induced the dissociation of RB1CC1 from DRMs and its subsequent nuclear translocation, contributing to ferroptosis of prostate cancer cells."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ACSL4 • GPX4 • RB1 • RB1CC1 • SLC7A11

Polydopamine-Coated Surfaces Promote Adhesion, Migration, Proliferation, Chemoresistance, Stemness, and Epithelial-Mesenchymal Transition of Human Prostate Cancer Cell Lines In Vitro via Integrin α2β1-FAK-JNK Signaling. (PubMed, Int J Mol Sci) - "Pharmacological inhibition of integrin α2β1 (BTT-3033), FAK (PF573228) and JNK (SP600125) effectively abrogated PDA-induced malignant phenotypes and restored chemosensitivity to cabazitaxel, cisplatin, docetaxel, curcumin, and enzalutamide. Collectively, these findings identify PDA-coated surfaces as a simple, efficient, and reductionist in vitro platform for studying adhesion-mediated signaling and phenotypic plasticity in PC cells, while acknowledging that further validation in three-dimensional (3D) and patient-derived models will be required to establish in vivo relevance."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ABCB1 • CD133 • CD44 • KIT • MMP2 • MMP9 • NANOG • POU5F1 • SOX2

Network pharmacology and cell experiments reveal induction of apoptosis and autophagy of lung adenocarcinoma cells by Blaps rynchopetera via MAPK/JNK signaling pathway (PubMed, Zhongguo Zhong Yao Za Zhi) - "The autophagy inhibitor chloroquine enhanced the pro-apoptotic effect of B. rynchopetera. Additionally, the c-Jun N-terminal kinase(JNK) inhibitor(SP600125) suppressed the activation of the JNK pathway as well as B. rynchopetera-induced apoptosis and autophagy. In conclusion, B. rynchopetera activates the MAPK/JNK pathway to induce apoptosis and autophagy, thereby exerting the therapeutic effect on LUAD."

IO biomarker • Journal • B Cell Lymphoma • Lung Adenocarcinoma • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BCL2 • BECN1 • CASP3 • MAPK8 • PCNA

CSRNP1 Promotes Apoptosis and Mitochondrial Dysfunction via ROS-Mediated JNK/p38 MAPK Pathway Activation in Hepatocellular Carcinoma. (PubMed, Oncol Res) - "WB was used to assess activation of the c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) pathway, and pathway dependence was examined using the ROS scavenger N-Acetylcysteine (NAC) and the JNK inhibitor SP600125. It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner. These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC."

Journal • Hepatocellular Cancer • Metabolic Disorders • Oncology • Solid Tumor • FANCF • MAPK8 • NR4A1

Conversion the Intestinal Smooth Muscle Cells of Hirschsprung's Disease into Enteric Neurons-like Cells by Small Molecule Compounds. (PubMed, J Pediatr Surg) - "Our findings collectively present a transgene-free and chemical-only approach for the direct reprogramming of ISMCs into neuron-like cells. This method offers an alternative strategy for replenishing the ENS in cases of HSCR."

Journal • Gastrointestinal Disorder • Pediatrics • Rare Diseases • Transplantation

Basic Science and Pathogenesis. (PubMed, Alzheimers Dement) - "Traditional cerebral organoid models have been limited by the difficulty in differentiating microglia or the prolonged periods required for their maturation. Here, we established a more physiologically relevant system by co-culturing organoids and microglia at a developmentally analogous timepoint, enhancing our ability to mimic in vivo brain processes. Moreover, by employing AD patient-derived iPSCs, we successfully recapitulated disease-associated inflammatory phenotypes, highlighting the potential of this platform for both mechanistic studies and drug screening in the context of AD."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Inflammation • IL1B • IL6 • TNFA

Regulation of Renal Transporters by Pro-inflammatory Cytokines in Human Proximal Tubular Epithelial Cells: Identification of the Perpetrator and Mechanisms. (PubMed, bioRxiv) - "To determine mechanisms of these effects, selective MAPK/NF-κB inhibitors (ERK [PD98059], p38 MAPK [SB203580], JNK [SP600125], and NF-κB [PDTC]), individually or as a cocktail, were used. These data provide quantitative inputs for physiologically based pharmacokinetic models to predict how inflammation alters renal transporter-mediated drug clearance, informing dose adjustment and risk assessment for disease-drug and drug-drug interactions in patients with inflammatory kidney disease or systemic infections. They also highlight signaling nodes where anti-inflammatory therapies might inadvertently modify renal drug transport."

Journal • Infectious Disease • Inflammation • Nephrology • Renal Disease • ABCC3 • IFNG • IL10 • IL1B • IL4 • IL6 • SLC22A2 • TNFA

AP-1 promotes oncogenic transcription in lung cancer cells by bridging promoter-enhancer interactions. (PubMed, Cancer Gene Ther) - "Pharmacological inhibition of AP-1, either directly via AP-1 inhibitor SR11302 or indirectly through its upstream JNK pathway inhibition via SP600125, suppressed AP-1-driven oncogenic transcription and reduced promoter-enhancer looping. Our findings highlight the pivotal role of AP-1 in oncogenic transcription in NSCLC, revealing that transcription factors enhance oncogene expression by facilitating promoter-enhancer interactions."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma

Dexamethasone regulates gene expression in chondrocytes through MKP-1 and downregulates cholesterol hydroxylases CH25H and CYP7B1. (PubMed, Inflamm Res) - "In conjunction with previous findings, the current data substantiate the role of MKP-1 as a protective factor in chondrocytes and highlight its potential as a therapeutic target for the treatment of osteoarthritis, because increased levels of cholesterol and its metabolism by CH25H and CYP7B1 are involved in the pathogenesis of OA, particularly in its obesity-associated phenotype."

Journal • Genetic Disorders • Immunology • Obesity • Orthopedics • Osteoarthritis • Pain • Rheumatology • IL1B

Integrin-specific signaling drives ER stress-dependent atherogenic endothelial activation. (PubMed, Redox Biol) - "However, pharmacological inhibition of ER stress using TUDCA suppresses proinflammatory and metabolic gene expression (bulk RNA-seq), without affecting NF-κB activation. Blocking this pathway using a JNK inhibitor (SP600125) or dominant-negative c-Jun (TAM67) abrogates inflammatory gene expression following oxLDL or disturbed flow. Together, these findings identify a novel mechanism by which fibronectin-integrin signaling promotes ER stress in response to mechanical and metabolic stressors, amplifying endothelial inflammation through JNK-c-Jun signaling."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • TLN1

RAB3GAP2 silencing alleviates oxidative stress in cataracts by enhancing Mfn2-mediated mitochondrial autophagy by activating JNK/STAT3. (PubMed, Int J Biol Macromol) - "Further in vitro studies revealed that SP600125 treatment reversed the effects of RAB3GAP2 silencing on cataract development, the promotion of Mfn2 and mitochondrial autophagy, and the activation and nucleation of STAT3...These findings suggest that RAB3GAP2 silencing can mitigate oxidative stress to prevent cataract development, probably by facilitating Mfn2-mediated mitochondrial autophagy by activating JNK/STAT3. It may be a promising target for treating cataracts."

Journal • Cataract • Ophthalmology • MFN2 • STAT3

Protopanaxadiol induces apoptosis through JNK signaling pathway and targeting MLK3 in human melanoma. (PubMed, J Ginseng Res) - "Inhibition of JNK with SP600125 reversed PPD-induced apoptosis, indicating that JNK signaling plays a critical role...Our findings revealed that PPD exerts potent anti-melanoma effects by directly targeting MLK3 and activating the MLK3-JNK signaling pathway, leading to apoptosis. These results provide novel insights into the molecular mechanism of PPD and suggest its potential as a therapeutic agent for melanoma treatment."

Journal • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • MAP3K11

DHCR24 knockdown-induced cellular cholesterol deficiency triggers tau hyperphosphorylation at Thr181, Ser199 and Ser202/Thr205 via p38 MAPK/JNK signaling. (PubMed, Cell Signal) - "Both compounds restored tau phosphorylation to baseline in a concentration-dependent manner, with maximal suppression at 40 μM (SB203580) and 20-40 μM (SP600125). Collectively, these data establish DHCR24-controlled cholesterol homeostasis as a molecular rheostat of tau pathology through p38/JNK signaling, and nominate this axis for therapeutic intervention in AD."

Journal • Alzheimer's Disease • CNS Disorders • Neuroblastoma • Oncology • Solid Tumor

Integrin–ER Stress Crosstalk Links Mechanical and Metabolic Stress to Vascular Inflammation (AHA 2025) - "However, pharmacological inhibition of ER stress using TUDCA suppresses proinflammatory and metabolic gene expression (bulk RNA-seq), without affecting NF-κB activation. Blocking this pathway using a JNK inhibitor (SP600125) or dominant-negative c-Jun (TAM67) abrogates inflammatory gene expression following oxLDL or disturbed flow. Together, these findings identify a novel mechanism by which fibronectin–integrin signaling promotes ER stress in response to mechanical and metabolic stressors, amplifying endothelial inflammation through JNK–c-Jun signaling and contributing to atherogenesis."

Late-breaking abstract • Atherosclerosis • Dyslipidemia • Inflammation • TLN1

c-Jun inhibition mitigates chemotherapy-induced neurotoxicity in iPSC-derived sensory neurons. (PubMed, Cell Death Discov) - "Administration of various chemotherapeutic agents (i.e., paclitaxel, vincristine, bortezomib and cisplatin) at clinically applicable concentrations resulted in reduced cell viability, axonal degeneration, electrophysiological dysfunction and increased levels of phosphorylated c-Jun in iPSC-DSN...To test whether c-Jun plays a central role in the development of CIPN, we applied the small molecule inhibitor of the Jun N-terminal kinase, SP600125, to iPSC-DSN treated with neurotoxic chemotherapy. c-Jun inhibition prevented chemotherapy-induced neurotoxicity by preserving cell viability, axonal integrity and electrophysiological function of iPSC-DSN. These findings identify c-Jun as a key mediator of CIPN pathophysiology across multiple drug types and present preclinical evidence that c-Jun inhibition is an attractive therapeutic target to prevent CIPN."

Journal • Oncology • Pain

Ursolic acid sensitizes bladder cancer to gemcitabine chemotherapy by concurrently targeting PI3K/AKT and JNK pathways. (PubMed, Transl Androl Urol) - "Pharmacological modulators (SC79, SP600125) were used to verify pathway roles. UA sensitizes BCa to GEM chemotherapy by promoting apoptosis, mediated through PI3K/AKT inactivation and JNK activation. These findings highlight UA as a promising adjunct to GEM therapy, warranting further clinical exploration."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CASP3 • MAPK8

Chemical Genetics with SP600125 Reveals That Mps1 Protein Kinase Works as a Regulatory Element in Post-embryonic Development of the Arabidopsis thaliana Root SystemAn Insight into Plant Cell Cycle Control. (PubMed, ACS Omega) - "Our experiments open new possibilities for understanding the mechanisms of the Mps1 protein using plants as experimental models. They also show that chemical genetics is a robust alternative for studies of plant development."

Journal • Oncology

SARM1 deficiency promotes depressive-like behavior and neuroinflammation through JNK/STING/TBK1 signaling. (PubMed, Int Immunopharmacol) - "Furthermore, Pharmacological inhibition of JNK with SP600125 in SARM1 knockdown mice effectively alleviated depressive-like behaviors, reduced hippocampal ROS and IL-1β, suppressed p-p38/p-NF-κB/NLRP3, and unexpectedly downregulated p-STING/p-TBK1 while improving PSD95 levels. These findings suggest that SARM1 deficiency drives neuroinflammation and depressive phenotypes through dysregulated JNK/STING/TBK1 signaling, highlighting this pathway as a potential therapeutic target for neuroinflammation-associated depression."

Journal • CNS Disorders • Depression • Inflammation • Psychiatry • DLG4 • IL1B • NLRP3 • SOD2 • STING • TBK1

Synthesis and evaluation of 8-(benzyloxy)-5,7-dibromo-2-methylquinoline derivatives as inducers of apoptosis in triple-negative breast cancer MDA-MB-468 cells via MKK7-JNK pathway activation. (PubMed, Bioorg Chem) - "Treatment with 10l significantly increased phospho-JNK (p-JNK) levels, and blockage of JNK signaling by either pharmacological inhibitor SP600125 or JNK siRNA abolished its pro-apoptotic effect, demonstrating that JNK activation was critical for 10l-induced cell death. Notably, the major kinase upstream of JNK MKK7 was activated under 10l treatment. All these data suggested that compound 10l was capable of inducing apoptosis via activating MKK7-JNK pathway, supporting its potential as a therapeutic candidate for TNBC treatment."

Journal • Breast Cancer • Liver Cancer • Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Deubiquitinating enzyme USP42 promotes breast cancer progression by inhibiting JNK/p38-mediated apoptosis. (PubMed, Sci Rep) - "Treatment with SP600125 (JNK inhibitor) or SB203580 (p38 MAPK inhibitor) effectively recused JNK and p38 activation. Both inhibitors also reduced the apoptotic cell population, which was upregulated by USP42 silencing. These findings highlight USP42 promotes breast cancer progression by reducing JNK and p38 activation and inhibiting apoptosis, suggesting its potential as a therapeutic target in breast cancer treatment."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BAX • BCL2 • CASP3 • USP4 • USP42

The skin hydration and anti-ageing benefits of Ectoine, achieved through enhanced Src-ERK-mediated HAS-2 and JNK-driven AQP-3 expression in human keratinocytes, along with the inhibition of MMP-1-induced collagen-I degradation in human fibroblasts, both with and without UVB irradiation. (PubMed, Int J Cosmet Sci) - "We demonstrated that Ectoine exerts skin hydration effects without or with UVB exposure in human skin keratinocyte (HaCaT) cells and anti-ageing in fibroblast (Hs68) cells. Therefore, Ectoine could serve as a potential natural compound in cosmetic preparations for skin hydration and anti-ageing."

Journal • MAPK1 • MMP1

Transcriptomic-Driven Drug Repurposing Reveals SP600125 as a Promising Drug Candidate for the Treatment of Glial-Mesenchymal Transition in Glioblastoma. (PubMed, Int J Mol Sci) - "Further ranking according to their blood-brain barrier permeability, as well as structural and transcriptomic similarities to known anti-GBM drugs, revealed SP600125, vemurafenib, FG-7142, dibenzoylmethane, and phensuximide as the most promising for GMT inhibition. In vitro validation showed that SP600125, which is most closely associated with GMT-related hub genes, effectively inhibited TGF-β1- and chemical hypoxia-induced GMT in U87 GBM cells by reducing morphological changes, migration, vasculogenic mimicry, and mesenchymal marker expression. These results clearly demonstrate the applicability of connectivity mapping as a powerful tool to accelerate the discovery of effective GMT-targeting therapies for GBM and significantly expand our understanding of the antitumor potential of SP600125."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • TGFB1