Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: STAT3 inhibition by SP2509 attenuates orthotopic tongue tumors: 4MOSC1 primary cells derived from tobacco carcinogen 4NQO-subjected tongue tumors were injected orthotopically and treated with SP2509. RNA-seq analysis after treatment of SP2509 in orthotopic 4MOSC1 syngeneic model. a Clinical cancer stage protein expression of LSD1 and STAT3 from CPTAC database. b Fold change of KDM1A and STAT3 in cancer cells like CAL27 and HSC3 in comparison with normal epithelial cells. c The tongue tumor volume of mice topically treated with SP2509 inhibits tumor volume. d The gross pathological phenotype, H&E staining of tongue treated with SP2509, showing reduced pathological lesions. “ns” P > 0.05, * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.000 1

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Inhibition, Derivative Assay, Injection, RNA Sequencing, Expressing, Comparison, Staining

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: STAT3 inhibition by SP2509 reduced cell cycle progression and promotes immune response. a Fold change of Kdm1a, Stat3 , and Ctla4 mRNA expression after treatment with SP2509 in mice OSCC preneoplasia. b Altered STAT3 protein expression in HSC3 compared to normal epithelial cells, and KDM1A knockout. c Gene set enrichment analysis (gene ontology) shows reduction in cell division and elevation in immune response when treated with SP2509. d Validation of G0/G1 cell cycle arrest after SP2509 and sg KDM1A treatment to HSC3 cells. Statistical analyses were performed using a t-test and one-way ANOVA. “ns” P > 0.05, * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.000 1

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Inhibition, Expressing, Knock-Out, Biomarker Discovery

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: SP2509 has a unique mechanism to promote infiltration of CD8+ T cells in tongue OSCC and inhibiting immunosuppressive CTLA4+ CD25+ T cells: LSD1 regulates tumor immune microenvironment and inhibition with SP2509 facilitates infiltration of various immune cell types: a SP2509 promotes infiltration of CD45+, TCRβ+, CD4+, and CD8+ T cells, and b Reduces CTLA4+ CD25+ (of CD4+ T cells) immunosuppressive cells in OSCC. c Secreted cytokines measured from serum samples showing a significant increase in proinflammatory cytokines like IFNβ, IFNγ, and IL9 in the SP2509 treatment group. “ns” P > 0.05, * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.000 1

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Inhibition

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: SP2509 treatment increases IFNγ producing T cells in a co-culture model. a Increased levels of CD8+ and CD4+ T cells along with IFNγ (in CD8+ and CD4+ T cells) in SP2509 treated HSC3 and human PBMC co-culture model. b Increased levels of CD8+ and CD4+ T cells along with IFNγ (in CD8+ and CD4+ T cells) in KDM1A deleted HSC3 and human PBMC co-culture model. “ns” P > 0.05, * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.000 1

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Co-Culture Assay

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: In combination with antiPD1 immunotherapy, LSD1 inhibition shows significant CD8+ T cell infiltration and activation: (a-b) 4NQO mice model treated with AntiPD1, SP2509, and AntiPD1 + SP2509 showing; a Variable levels of CD8+ T cells, PD1+ CD8+ T cells, and IFNγ+ CD8+ T cells, b Variable levels of CD4+ T cells, and IFNγ+ CD4+ T cells, and c Reduced levels of PD-L1+ epithelial cells. d Kaplan-Meier survival analysis showing reduced overall survival in KDM1A high, and KDM1A-STAT3 high| CD8A low expressing patient groups. Statistical analyses were performed by t-test, one-way ANOVA, and Log-rank t-test. “ns” P > 0.05, * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.000 1

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Inhibition, Activation Assay, Expressing

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: Proof of principle study showing feline spontaneous natural OSCC post-treatment with Seclidemstat shows safety of LSD1 inhibition compared to pre-treatment: To evaluate safety and mechanism of LSD1, Seclidemstat applied to client-owned cats in veterinary clinical studies. a Illustration of experimental design to evaluate the safety of Seclidemstat in an 11-year-old female owner-owned cat that had surgically excised primary OSCC, treated with Seclidemstat post-10 days of surgery, and analyzed for veterinary clinical parameters. b Complete blood count (CBC) and blood chemistry panel show increased lymphocytes, reduced monocytes and neutrophils, and reduced AST/ALT ratio (Pearson correlation)

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Inhibition

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: Feline spontaneous natural OSCC post-treatment with Seclidemstat shows efficacy of LSD1 inhibition compared to pre-treatment: a Illustration of an experimental plan to evaluate the Seclidemstat-inhibited STAT3 network in feline patients with progressive OSCC and visible tongue tumors recruited to study and treated with Seclidemstat for 56 days. b Volcano plot representing differentially expressed genes in pre- and post-Seclidemstat treatment highlighted significant downregulation of STAT3, EGFR , and immune checkpoint gene CTLA4 , whereas IRF3 was upregulated. c IPA analysis showed that downregulation in the EGFR-STAT3 pathway leads to CD8+ T cell proliferation and activation. “ns” P > 0.05, * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.000 1

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Inhibition, Activation Assay

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: LSD1 promotes STAT3 mediated OSCC progression: a , b HSC3 cells treated with SP2509 for 24 h and IL6 for 30- and 60 min shows reduced phosphorylated STAT3 (Tyr705) levels as evaluated by phospho-flow cytometry. c H&E staining of tongue tissue sections in Kdm1a −/− +4NQO shows a reduction in the pathological lesion on the tongue after 18 weeks compared to the Kdm1a fl/fl + 4NQO control. d H&E staining of tongue tissue sections isolated from mice with topical application of SP2509 inhibits pathological features of OSCC (quantification and evaluation performed blindly by a board-certified oral pathologist). Statistical analyses were performed by t-test and one-way ANOVA. “ns” P > 0.05, * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.000 1

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Flow Cytometry, Staining, Control, Isolation

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: LSD1 promotes STAT3 phosphorylation and CTLA4+ immune cells: a Phosho-STAT3 (Tyr705) immunostaining of Kdm1a −/− + 4NQO and Kdm1a fl/fl + 4NQO (upper panel), and Kdm1a fl/fl + 4NQO + SP2509 and Kdm1a fl/fl + 4NQO+Vehicle treated C57BL/6J mice (lower panel), and their respective quantifications. b Accumulation and quantification of CTLA4+ immune cells at the tumor site in Kdm1a fl/fl and Kdm1a −/− mice tongue. Statistical analyses were performed by t-test. “ns” P > 0.05, * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.000 1

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Phospho-proteomics, Immunostaining

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: Proteomics analysis showing Kdm1a knockout impairs STAT3 protein network: Global proteomics of tongue protein lysate from Kdm1a −/− + 4NQO compared to Kdm1a fl/fl + 4NQO. a Volcano plot showing downregulation of STAT3 along with top dysregulated genes. b IPA analysis of candidate genes involved in EGFR-related network. c IPA analysis shows affected STAT3-associated events and well as increased tumor suppressor events

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Knock-Out

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: Proteomics analysis showing LSD1 inhibition impairs STAT3 protein and phospho-protein network: a Global proteomics of tongue tumor protein lysate from 4MOSC1 syngeneic mouse model showing SP2509 treatment reduces LSD1 and STAT3, whereas increased NFATc1 and IRF3. b Phosphoproteomics analysis of 4MOSC1 tumors treated with SP2509 reversed phosphorylated oncoproteins expression shown in the heat map, including phospho-CDK7 (Tyr170). c Kinase-substrate enrichment analysis (KSEA) in Phosphomatics tool reveals the kinase activity-based z-score (activation/deactivation) on the reduced activity for phosphorylated CDK7

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Inhibition, Phospho-proteomics, Expressing, Activity Assay, Activation Assay

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: Phosphoproteomics analysis showing LSD1 inhibition impairs CDK7 and EGFR-STAT3 network: a Kinase substrate interaction analysis in SP2509 treated groups shows inhibition of CDK7 phosphorylation, which has various substrates, including other CDKs and eukaryotic translation initiation factors. b IPA analysis generated by global proteomics data shows that SP2509 reduces the EGFR-STAT3 network, whereas upregulation of NFATc1 results in accumulation of inflammatory leukocyte network

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Phospho-proteomics, Inhibition, Generated

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: CDK7 is a key mediator of LSD1-induced STAT3 expression: RT-qPCR analysis to evaluate the effect of LSD1, STAT3, or CDK7 inhibitors on expression KDM1A, STAT3 , and CDK7 expression in; a HSC3 cells, and b CAL27 cells. RT-qPCR analysis to evaluate the effect of genetic knockout of KDM1A, STAT3 , or CDK7 on expression of KDM1A, STAT3 , and CDK7 in; c HSC3 cells, and d CAL27 cells. “ns” P > 0.05, * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.000 1

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Expressing, Quantitative RT-PCR, Knock-Out

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: Impact on phosphorylation of CDK7 and methylation of H3K4 and H3K9 after LSD1 inhibition: a Effect on phospho-CDK7 (T170) after LSD1, STAT3 and CDK7 inhibition. b Status of H3K4 and H3K9 methylation on STAT3 and CDK7. Statistical analysis was performed by t -test and one-way ANOVA. “ns” P > 0.05, * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.000 1

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Phospho-proteomics, Methylation, Inhibition

Journal: International Journal of Oral Science

Article Title: Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression

doi: 10.1038/s41368-025-00363-x

Figure Lengend Snippet: Graphical Abstract. The potential mechanism after blocking LSD1 inhibits novel CDK7 phospho-protein networks and STAT3 signaling ultimately promotes CD8+ T cell infiltration and activation by relieving CTLA4-mediated immunosuppression

Article Snippet: – The LSD1 inhibitor SP2509 is similar to its clinical candidate SP2577 (Seclidemstat; Salarius Pharmaceutical).

Techniques: Blocking Assay, Activation Assay