T-5224 / Fujifilm Holdings - LARVOL DELTA

FOSL2-ANXA1 Axis Maintains the Survival of Multiple Myeloma Cells with Low BCMA Expression (IMS 2026) - "For translational purposes, the antagonist inhibiting AP-1 signaling, T-5224, was adopted... The data demonstrate that FOSL2 could serve as a key regulator of ANXA1 expression in the MM cells with low BCMA levels and support their survival. Targeting FOSL2 may be a strategy to combat BCMA-low MM cells."

IO biomarker • Hematological Malignancies • Multiple Myeloma • ANPEP • ANXA1 • ANXA5 • CD33 • FOSL2 • FOXM1 • GATA3 • SDC1

Lactate-associated H3K18la upregulates RNF166 to promote immune evasion in hepatocellular carcinoma by remodeling c-Jun ubiquitination. (PubMed, Apoptosis) - "Therapeutically, pharmacological inhibition of c-Jun with T-5224 enhanced the antitumor effect of anti-PD-L1 blockade. Collectively, our findings delineate a lactate-H3K18la-RNF166-c-Jun-PD-L1 axis that promotes immune evasion in HCC and suggest that targeting RNF166 or the RNF166-c-Jun axis may improve PD-1/PD-L1-based immunotherapy."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CD8 • JUN

Myeloid Activator Protein-1 Complex Contributes to Salt-Sensitive Hypertension. (PubMed, Circ Res) - "To test causality, we adoptively transferred PBMCs from salt-sensitive, salt-resistant, and salt-sensitive individuals pretreated with T5224 (a selective AP-1 inhibitor) into immunodeficient NSG-(KbDb)null (IA)null humanized mice, followed by assessment of blood pressure, vascular reactivity, kidney function, and immune infiltration...These findings identify AP-1 as a key transcriptional driver linking dietary sodium, immune activation, and salt-sensitivity of blood pressure. Targeting AP-1 signaling mitigates immune-mediated renal and vascular injury, highlighting a novel mechanistic pathway and a therapeutic target for salt-sensitive hypertension."

Journal • Cardiovascular • Hypertension • Inflammation • FOS • JUN • JUNB

Targeting the Jun-Irf8-CD36 axis attenuates fibrotic scar formation and promotes functional recovery after spinal cord injury. (PubMed, Burns Trauma) - "The c-Jun-Irf8-CD36 axis serves as a pivotal regulator of fibrotic scar formation after SCI. Targeting this pathway through CD36 inhibition (SAB) or AP-1/c-Jun blockade (T5224) attenuates fibrosis, remodels the scar microenvironment, enhances tissue repair, and promotes functional recovery, highlighting a promising therapeutic strategy for central nervous system injury."

Journal • CNS Disorders • Fibrosis • Immunology • Orthopedics • CD36 • IRF8 • JUN • SCARB1

THE EPSTEIN-BARR VIRUS LMP1 PROMOTES B CELL LYMPHOMA BY ENHANCING AICDA VIA AP-1 SIGNALLING (EHA 2026) - "The use of approved AP-1 inhibitors, such as T-5224, which blocks AP-1 binding to DNA, may be a useful addition in B-cell lymphoma therapy, and other EBV- driven malignancies. Future work could use pre-clinical laboratory investigations to interrogate this further."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Epstein-Barr Virus Infections • Hematological Malignancies • Infectious Disease • Lymphoma • Non-Hodgkin’s Lymphoma • AICDA • FOXP3 • JUNB • MYC • STAT4

The CEBPB-AP-1 (JunB/Fos) Axis Drives Neuroinflammation and Microglial Dysfunction Via TNF Signaling in Ischemic Stroke. (PubMed, Inflammation) - "In vivo, T-5224 treatment in tFCI mice suppressed neuroinflammation, reduced neuronal apoptosis in the striatum and cortex, promoted a restorative microglial phenotype, and improved long-term sensorimotor and cognitive function. These findings establish the CEBPB/AP-1 axis as a critical driver of neuroinflammation in ischemic stroke and highlight it as a promising therapeutic target."

Journal • Cardiovascular • Inflammation • Ischemic stroke • CEBPB • IL1B • JUNB

Cerebellar Microglial Metabolic–Inflammatory Coupling Drives Network Progression in Temporal Lobe Epilepsy: Multimodal PET and Targeted FOS Inhibition (SNMMI 2026) - "In a lithium–pilocarpine rat TLE model, longitudinal [18F]FDG microPET/CT was performed at acute (day 1), latent (day 14), and chronic (day 60) stages; chronic-phase [18F]DPA-714 (TSPO) microPET/CT quantified microglial activation (SUVr referenced to pons)...Cerebellar RNA-seq with KEGG enrichment identified upstream regulators; mechanistic validation used stereotactic cerebellar delivery of minocycline or the FOS inhibitor T-5224 followed by 7-day seizure monitoring and cognitive testing (novel object recognition and Morris water maze)... These data identify a cerebellar microglia-driven metabolic–inflammatory coupling axis as a mechanistic driver of TLE network progression and behavioral comorbidity. Dual-tracer PET (FDG + TSPO) provides a translatable imaging readout of this axis, and FOS-dependent signaling represents a tractable target for precision neuromodulation in drug-resistant TLE."

CNS Disorders • Epilepsy • Inflammation • CD163 • CD200R1 • CD86 • FCGR2A • FCGR2B • IFNG • IL6 • SLC2A1 • SLC2A3 • TNFA

Pharmacological targeting of the TLR8/AP-1 axis ameliorates scleroderma skin inflammation and fibrosis by suppressing monocyte-mediated endothelial injury. (PubMed, Life Sci) - "The TLR8/AP-1 axis drives monocyte-mediated endothelial injury in SSc. Pharmacological AP-1 inhibition disrupts this pathogenic monocyte-endothelial crosstalk, offering a promising therapeutic strategy against SSc skin inflammation and fibrosis."

IO biomarker • Journal • Cardiovascular • Dermatitis • Fibrosis • Immunology • Inflammation • Rheumatology • Scleroderma • Systemic Sclerosis • CD14 • ITGB1 • ITGB2 • TLR8

Curcumin suppresses HNSCC tumorigenesis through directly targeting FOSL1/JUN. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "Comparative analyses of three anti-cancer natural products, including curcumin, gingerol, and allicin, revealed that only curcumin robustly inhibited HNSCC cell proliferation, invasion, and cancer stem cell self-renewal, with potency comparable or superior to cisplatin. At last, curcumin treatment profoundly suppressed HNSCC tumor growth in xenograft model and exhibited superior efficacy compared with the FOSL1/AP-1 inhibitor T-5224, without apparent toxicity. Collectively, our findings identify FOSL1/JUN complex as a direct molecular target of curcumin and uncover a novel mechanism by which this accessible natural product suppresses HNSCC tumorigenesis, supporting its potential as an affordable and safe therapeutic option for cancer treatment."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BMI1 • EGFR • FOSL1 • TP63

Parbendazole induces semaphorin 3A expression via JNK/c-Jun signaling pathway in normal human epidermal keratinocytes. (PubMed, J Dermatol Sci) - "Parbendazole dose-dependently induced Sema3A expression via the JNK/c-Jun signaling axis. Benzimidazole anthelmintics may have potential for developing new antipruritic drugs."

Journal • NGF • SEMA3A

WISP-3 promotes angiogenesis in non-small cell lung cancer through p38/JNK-c-Jun-mediated PDGF-A upregulation. (PubMed, J Cancer) - "Pharmacological inhibition of p38 (Adezmapimod), JNK (SP600125), or c-Jun (T-5224) effectively suppressed WISP-3-induced c-Jun activation, PDGF-A expression, and subsequent angiogenesis. Collectively, our findings identify a novel WISP-3/p38-JNK/c-Jun/PDGF-A signaling axis that drives vascular remodeling in NSCLC. Targeting WISP-3 or its downstream effectors may represent a promising therapeutic strategy for anti-angiogenic treatment in lung cancer."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Convergence of external and internal stressors on a stress-responsive enhancer of the Sonic hedgehog gene to induce hair disorders. (PubMed, Proc Natl Acad Sci U S A) - "Furthermore, two chemical agents SR11302 and T-5224 which suppress Egr1 expression both rescued the hair disorders under the various stressors. We propose that an Egr1-Shh axis integrates distinct stress signals and induces hair disorders via suppression of Shh gene expression, and provide a plausible strategy for therapeutic intervention. Our results establish a paradigm of how stress perturbs organ growth and regeneration through the regulation of key intrinsic morphogenetic factors."

Journal • Alopecia • Genetic Disorders • Obesity • EGR1 • SHH

Single-cell RNA sequencing-guided drug discovery to alleviate radiotherapy-induced esophageal toxicity. (PubMed, Acta Pharm Sin B) - No abstract available

Journal

Identification of cryosensitive niches and a targetable FOS/AP‑1 program in the human ovarian cortex by single‑cell and spatial transcriptomics. (PubMed, BMC Med) - "Stromal and perivascular cells are the main cell types that are sensitive to ovarian cryopreservation. The FOS/AP-1 pathway is markedly activated after, suggesting the exacerbation of metabolic impairment. In oocytes within the ovarian cortex, the cell cycle and meiosis-related physiological processes were the primary processes affected."

Journal • PTGDS

Spatial transcriptomics identifies differentiation, lipid metabolism, and retinoid pathway alterations in acne vulgaris. (PubMed, JCI Insight) - "Finally, we demonstrated that an AP-1 inhibitor, T-5224, downregulates FABP5 in human keratinocytes and reduces pustule formation in a mouse model of high-fat diet-induced folliculitis. Altogether, these findings indicate that altered lipogenesis, retinoid signaling, and keratinocyte differentiation are key features of acne, and nominate AP-1 and FABP5 as potential therapeutic targets."

Journal • Acne Vulgaris • Dermatology • Metabolic Disorders • FABP5 • PPARG

Activator protein-1 (AP-1) inhibition prevents endothelial to mesenchymal transition in diabetes-associated atherosclerosis: a translational study. (PubMed, Cardiovasc Diabetol) - "This study identifies AP-1 inhibition with T-5224 as a potential therapeutic approach for EndMT resulting in reduced atherosclerosis in diabetes. The use of human serum underscores the translational relevance of these findings."

Journal • Atherosclerosis • Cardiovascular • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • APOE • TNFA

Basic Science and Pathogenesis. (PubMed, Alzheimers Dement) - "This study replicated the associations of SORL1, CR1, ADAM17, RASGEF1C, SPI1, and ADAMTS1 with AD risk and protection are found in Cuban Americans. The large effect of the APOE4 aligns with its established role in AD pathogenesis across different populations. These results enhance our overall understanding of the genetic underpinnings of AD and support the advancement of targeted research and therapeutic interventions."

Journal • Alzheimer's Disease • CNS Disorders • ADAM17 • ADAMTS1 • APOE • SORL1 • SPI1

Targeting tumour-astrocyte crosstalk for rational identification of novel therapeutic targets for medulloblastoma and atypical teratoid/ rhabdoid tumours (SNO 2025) - "3D migration studies found that T-5224 (FOS inhibitor) and AZD8055 significantly reduced migration of spheroids in vitro for MB cells.Delivery of T-5224 and AZD8055 to a d425 resection model demonstrated tolerability. Similarly, delivery of Tiplaxtinin and AZD8055 conferred tolerability in a BT12 resection model and a survival advantage was indicated in groups treated with AZD8055 alone."

Brain Cancer • Medulloblastoma • Oncology • Rhabdoid Tumor • Sarcoma • Solid Tumor • COL1A1 • MMP2 • NOTCH3 • S100A10 • SERPINE1 • SOCS3 • TGFBR2

Uncovering the role of c-Fos in the bidirectional relationship between depression/anxiety behaviors and α-synuclein propagation in Parkinson's disease. (PubMed, Neurotherapeutics) - "Pharmacological inhibition of c-Fos with T5224 mitigated both behavioral and pathological changes, and mGluR5 activation was found to partially contribute to c-Fos induction and α-syn spread. Together, these findings highlight a feedback interaction between affective symptoms and α-syn pathology in PD, mediated in part by neuronal activity-dependent mechanisms involving c-Fos and mGluR5, and suggest that early interventions targeting both neuronal activity and α-syn propagation may slow PD progression and improve patient quality of life."

Journal • CNS Disorders • Depression • Mood Disorders • Movement Disorders • Parkinson's Disease • Psychiatry • FOS

Targeting tumour-astrocyte crosstalk for rational identification of novel therapeutic targets for medulloblastoma and atypical teratoid/ rhabdoid tumours (WFNOS 2025) - "3D migration studies found that T-5224 (FOS inhibitor) and AZD8055 significantly reduced migration of spheroids in vitro for MB cells.Delivery of T-5224 and AZD8055 to a d425 resection model demonstrated tolerability. Similarly, delivery of Tiplaxtinin and AZD8055 conferred tolerability in a BT12 resection model and a survival advantage was indicated in groups treated with AZD8055 alone."

Brain Cancer • Medulloblastoma • Rhabdoid Tumor • Sarcoma • Solid Tumor • COL1A1 • MMP2 • NOTCH3 • S100A10 • SERPINE1 • SOCS3 • TGFBR2

Ginsenoside Rb1 alleviates atherosclerosis by modulating vascular smooth muscle cell proliferation, foam cell formation, and autophagy. (PubMed, Phytomedicine) - "Rb1 mitigates atherosclerosis by inhibiting VSMC proliferation and foam formation through suppression of c-JUN/AP-1-mediated LOX-1 transcription and activation of autophagy. These actions support Rb1 as a promising phytotherapeutic for plaque attenuation and stabilization."

Journal • Atherosclerosis • Cardiovascular • Inflammation • APOE • PACERR • PTGS2

Multi-Omics Analysis Reveals That TET2 Loss Epigenetically Primes Monocytes for Inflammatory Responses Via AP-1 Signaling (ASH 2023) - "We found that the AP-1 inhibitor T5224 dose dependently reduced the expansion of Tet2KO Hoxb8 progenitor cells in base media and inhibited the IL-6 mediated expansion of Tet2KO Hoxb8 cells...Starting at the GMP stage, we see increases in phosphoprotein responses to IFNγ, and then the addition of hypersensitivity to IL-6 in monocytes. TET2 loss leads to an increase in accessible AP-1 motifs in Tet2KO cells, while inhibition of AP-1 reduces fitness of cells, suggesting a possible therapeutic strategy for TET2-mutated myeloid malignancy."

Hematological Malignancies • Immunology • Inflammation • Myelodysplastic Syndrome • Oncology • CD34 • CEBPA • FOSL2 • IFNA1 • IFNG • IL6 • JUNB • PTPRC • RUNX1 • TET2

FOSL2-induced transcriptional activation of L1CAM promotes progression of lung adenocarcinoma via the PI3K/AKT/mTOR signaling pathway. (PubMed, Int Immunopharmacol) - "Treatment with the AP-1 inhibitor T5224 reduced proliferation of A549 cells. Moreover, knockdown of L1CAM attenuated the tumor-promoting effects of FOSL2 overexpression, indicating that L1CAM contributes to the oncogenic activity of FOSL2, possibly by mediating activation of the PI3K/AKT/mTOR signaling pathway."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • FOSL2 • L1CAM

BONE MARROW MESENCHYMAL STEM CELLS DRIVE NEUROBLASTOMA NORADRENERGIC-TO-MESENCHYMAL TRANSITION THROUGH AP-1-DEPENDENT TRANSCRIPTIONAL REPROGRAMMING (SIOP 2025) - "Functionally, T-5224 suppressed BMSCs-induced enhancements in migratory capacity (p < 0.01), invasive potential (p < 0.001), and doxorubicin chemoresistance (p < 0.05). Conclusions BMSCs drive NB NMT via AP-1, promoting metastasis and chemoresistance. Pharmacological inhibition of AP-1 by T-5224 reverses these effects, highlighting stromal-tumor crosstalk as a therapeutic target to combat aggressive NB progression."

Neuroblastoma • Solid Tumor • CD44 • JUNB

Modulation of the JNK/c-Jun/HSP27 Pathway in Cardiomyocytes under Chronic Stress-Induced Cardiac Dysfunction: Therapeutic Implications of Tauroursodeoxycholic Acid. (PubMed, Free Radic Biol Med) - "Elevated corticosterone levels in depression contribute to cardiac dysfunction through oxidative damage. TUDCA mitigates these effects via the JNK/c-Jun/HSP27 pathway, which offers potential therapeutic implications for depression-associated cardiac dysfunction."

IO biomarker • Journal • Cardiovascular • CNS Disorders • Depression • Fibrosis • Immunology • Psychiatry • BCL2 • HSPB1