T-5224 / Fujifilm Holdings - LARVOL DELTA

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

JunB orchestrates macrophage-fibroblast crosstalk in silica nanoparticle-induced pulmonary fibrosis. (PubMed, Ecotoxicol Environ Saf) - "Importantly, intraperitoneal administration of T-5224 substantially ameliorated pulmonary fibrosis in SiNPs-exposed mice, as evidenced by reduced collagen deposition and decreased expression of fibrotic markers. In conclusion, this study establishes JunB as a critical mediator of SiNPs-induced pulmonary fibrosis and demonstrates the therapeutic potential of JunB inhibition, which provides new insights for developing targeted treatments for lung fibrosis."

Journal • Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • JUNB

Formononetin Alleviates MNNG-Triggered Chronic Atrophic Gastritis: Its Potential Mechanisms. (PubMed, Comb Chem High Throughput Screen) - "FMN ameliorated the cell damage that MNNG triggered in GES-1 cells. The mechanism involved the anti-inflammatory and anti-apoptotic effects of FMN via modulation of the NCOA1/AP-1 signaling axis. The present preliminary study found FMN to exhibit a potential therapeutic effect against CAG."

Journal • Gastric Cancer • Gastrointestinal Disorder • Inflammation • Oncology • Peptic Ulcer • Solid Tumor • FOS • NCOA1

Transcription Factors and Methods for the Pharmacological Correction of Their Activity. (PubMed, Int J Mol Sci) - "p53, often mutated in cancer, is reactivated using MDM2 antagonist Nutlin-3, refunctionalizing compound APR-246, or stapled peptides. HIF-1α, which regulates hypoxic responses and angiogenesis, is inhibited by agents like acriflavine or stabilized in anemia therapies by HIF-PHD inhibitor roxadustat...AP-1, implicated in cancer and arthritis, can be inhibited by T-5224 or kinase inhibitors JNK and p38 MAPK...Challenges remain, including the structural inaccessibility of TFs, functional redundancy, off-target effects, and delivery barriers. Despite these challenges, transcription factor modulation is emerging as a viable and promising therapeutic approach, with ongoing research focusing on specificity, safety, and efficient delivery methods to realize its full clinical potential."

Journal • Review • CNS Disorders • Hematological Disorders • Immunology • Oncology • Rheumatology • Targeted Protein Degradation • HIF1A • STAT3 • STAT5 • STAT5AWqe

SF3A3 Drives Tumorigenesis in Endometrial Cancer by Enhancing c-FOS Expression and Represents a Potential Therapeutic Target. (PubMed, Adv Sci (Weinh)) - "Functionally, SF3A3 drives tumor progression by promoting cell proliferation, suppressing apoptosis, and enhancing cisplatin resistance in vitro and in vivo. The therapeutic potential of SF3A3 inhibition is further validated using patient-derived tumor-like cell clusters (PTCs), where PEITC and the c-FOS inhibitor T-5224 exhibit synergistic effects in suppressing EC. Collectively, our findings establish SF3A3 as a novel oncogenic regulator in EC and highlight PEITC, particularly in its hydrogel formulation, as a promising therapeutic strategy for improving clinical outcomes in EC patients."

Journal • Endometrial Cancer • Oncology • Solid Tumor • FOS

Induction of the zinc finger transcription factor GATA2 promotes kidney inflammation-related gene expression. (PubMed, J Biol Chem) - "Furthermore, the up-regulation of Csf1, Cxcl10, and Vcam1 following GATA2 induction was attenuated by the AP-1-specific inhibitor T-5224. Overall, this study is the first to determine genome-wide GATA2 occupancy and its impact on chromatin accessibility in kidney cells. These findings provide molecular insights into the role of GATA2 in kidney inflammation."

Journal • Inflammation • Nephrology • Renal Disease • CSF1 • CXCL10 • GATA2 • VCAM1

Single-cell transcriptomic analysis reveals AP-1 downregulation remodels bone marrow environment and contributes to osteopenia in ovariectomized mice. (PubMed, J Orthop Translat) - "AP-1 inhibitor T5224 was administered to validate its functional role in vivo, while in vitro experiments assessed AP-1 activation via estrogen receptor signaling under estrogen stimulation...AP-1 downregulation drives estrogen deficiency-related osteopenia by disrupting bone marrow homeostasis, primarily through excessive B cell expansion and elevated osteoclastogenic signaling. Targeting B cell proliferation via IL-7 blockade presents a potential therapeutic strategy for mitigating osteoporosis in estrogen-deficient conditions."

Journal • Preclinical • Osteoporosis • Rheumatology • ER • IL7 • JUNB • TNFSF11

c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment. (PubMed, Cells) - "We have previously shown that the upregulation of the AP-1 transcription factor c-FOS confers lenalidomide resistance by maintaining IRF4 expression in MM cells. In this study, we show that upregulated expression of c-FOS confers a poor prognosis and cancer stem cell-like features, including drug resistance, within BMME, both in vitro and in vivo, via IRF4 upregulation; and that inhibition of c-FOS by the AP-1 inhibitor, T-5224, prevents regeneration of MM cells via IRF4 downregulation in a murine serial transplantation assay. These results suggest a functional role for c-FOS in conferring cancer stem cell-like features to MM cells in the BMME for the first time. Therefore, c-FOS inhibition may be an effective treatment strategy for improving the outcomes of patients with MM by eliminating drug-resistant cancer stem cell-like MM cells in MRD."

Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Transplantation • FOS • IRF4

Cardiac Slc25a49-Mediated Energy Reprogramming Governs Doxorubicin-Induced Cardiomyopathy through the G6P-AP-1-Sln Axis. (PubMed, Adv Sci (Weinh)) - "Doxorubicin (Dox), a potent antitumor drug, is linked to cardiac toxicity. Strikingly, targeting of this axis with the AP-1 inhibitor T-5224 effectively improves survival and enhances cardiac function in Dox-induced cardiomyopathy. This study provides mechanistic insights into energy reprogramming that permits myocardial dysfunction, and thus provides a proof of concept for antienergy reprogramming therapy for Dox-induced cardiomyopathy through directly modulating G6P-AP-1-Sln axis."

Journal • Cardiomyopathy • Cardiovascular • Oncology

C-FOS promotes the formation of neutrophil extracellular traps and the recruitment of neutrophils in lung metastasis of triple-negative breast cancer. (PubMed, J Exp Clin Cancer Res) - "In summary, this study demonstrates that the ROS-p38-cFOS-PAD4 axis can increase NET formation in TNBC and promote the expression of inflammatory factors, facilitating neutrophil recruitment. Therefore, targeting this pathway may help inform new therapeutic strategies and provide new insights for immunotherapy in TNBC."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • FOS

A positive feedback loop of OTUD1 and c-Jun driven by leptin expedites stemness maintenance in ovarian cancer. (PubMed, Oncogene) - "Notably, the disruption of the positive feedback loop by targeting c-Jun or ASK1/JNK with T-5224, selonsertib, or ibrutinib markedly inhibited the leptin-induced stemness maintenance of OCSCs and tumorigenicity. Our findings reveal a crucial mechanism for leptin-mediated stemness maintenance and indicate that targeting c-Jun or the identified positive feedback loop has translational potential for ovarian cancer patients."

Journal • Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation • JUN • LEP • OTUD1

Postoperative adhesions are abrogated by a sustained-release anti-JUN therapeutic in preclinical models. (PubMed, Sci Transl Med) - "We have previously shown that signaling of the transcription factor JUN regulates adhesiogenesis and that a small-molecule JUN inhibitor (T-5224) decreases adhesion formation...Adhesion biology is similar across surgical sites, and, therefore, this formulation has potential for applicability across the body. The development of therapeutics to prevent adhesions is of paramount importance with potential for high-impact translation to patient care to address a common, unmet clinical need."

Journal • Preclinical • Fibrosis • Immunology • Infertility • Pain • Sexual Disorders

Genetic variants in the IFNGR2 locus associated with severe chronic Q fever. (PubMed, Hum Immunol) - "Four SNPs in the IFNGR2 locus, rs78407108 G > A, rs17879956 C > T, rs7277167 C > T, and rs9974603 C > A, showed a statistically significant association to chronic Q fever, resisting the Bonferroni correction...Given the direct bearing of IFNGR2 on IFN-γ signaling, the possible involvement of the associated variants with higher IFNGR2 expression could be in line with observations suggesting that IFN-γ production in chronic Q fever patients is significantly higher than in healthy controls. Further investigations are required to clarify the role of IFNGR2 signaling in association with chronic Q fever."

Journal • Infectious Disease • IFNAR2 • IFNG

EXPRESS: Curcumin relieves CFA-induced-inflammatory pain by inhibiting the AP-1/c-Jun-CCL2-CCR2 pathway in the spinal dorsal horn. (PubMed, Mol Pain) - "Intrathecal injection of the AP-1/c-Jun inhibitor T-5224, along with curcumin, resulted in a reduction in the levels of c-Jun, p-c-Jun, CCL2, and CCR2...CCL2/CCR2 acts as a downstream mediator of AP - 1/c - Jun. Curcumin can suppress the expression of AP - 1/c - Jun, thereby inhibiting the expression of CCL2 and CCR2 in the spinal dorsal horn and contributing to the treatment of inflammatory pain."

Journal • Inflammation • Pain • CCL2 • CCR2

Fenofibrate Reduces Ischemic Cerebral Edema via the Suppression of Aquaporin-4. (PubMed, J Biochem Mol Toxicol) - "The study aimed to investigate the neuroprotective effects of fenofibrate (FENO), a triglyceride-lowering drug, in rats with cerebral ischemia. Notably, the presence of the AP-1 specific inhibitor T5224 further promoted the effects of FENO in suppressing the expression of AQP4, implicating that the inhibitory effects of FENO on AQP4 expression are mediated by the p38/AP-1 signaling pathway. These findings suggest that FENO may have potential therapeutic benefits in stroke by targeting the p38/AP-1 signaling pathway and reducing AQP4 expression, thereby alleviating cerebral edema and inflammation."

Journal • Cardiovascular • Oncology • AQP4 • CCL2 • FOS • GFAP • IL6 • JUN • MPO • TNFA