selisistat (SEN-196) / AOP Orphan Pharma - LARVOL DELTA

SIRT1 Mediates the Effects of Sera from Athletes Who Engage in Aerobic Exercise Training in Activating Cells for Wound Healing. (PubMed, Biomedicines) - "Cell motility, angiogenesis and the expression of key biomarkers of cell activation were evaluated in the presence or absence of the selective SIRT1 inhibitor EX-527...Increased levels of differentiation markers, such as involucrin in the keratinocytes, FAP1α in the fibroblasts and CD31 in the endothelial cells, were observed with the MDR group sera compared to these values using the sed group sera. The ex vivo/in vitro approach used here links aerobic ET-induced SIRT1 activity to proper tissue regeneration."

Journal • CD31 • CDH1 • PECAM1 • SIRT1 • VCL

Integrated Metabolomics and Lipidomics Analysis Reveals the Mechanism Behind the Action of Chiglitazar on the Protection Against Sepsis-Induced Acute Lung Injury. (PubMed, Metabolites) - "Co-treatment with EX-527 in LPS-stimulated BEAS-2B cells and CLP rats inhibited the effects of chiglitazar on the aforementioned signaling pathways and worsened the protective effects of chiglitazar on lung injury, respectively. Chiglitazar alleviates SALI by restoring NAD+ and TG synthesis, highlighting the balancing of metabolism as a promising therapeutic strategy in the management of SALI."

Journal • Acute Lung Injury • Infectious Disease • Metabolic Disorders • Respiratory Diseases • Septic Shock • PPARA

Neutrophils shape the therapeutic efficacy of sirtuin 1 activity modulators in murine influenza virus infection. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "The lung pathology in EX527-treated group with infection was strongly associated with the BAL Ly6G+TNF-α+ cells and the Sirt1 levels in Ly6Ghi neutrophils. Overall, the results showed that although the Sirt1 activator had a greater effect in normalizing the BM and blood neutrophils in severe IAV infection, its effectiveness was compromised locally by its failure to inhibit the expanded neutrophil pools to a degree that was less detrimental."

Journal • Preclinical • Infectious Disease • Influenza • Oncology • Respiratory Diseases • CXCR2 • IL1B • TNFA

Nobiletin potentially reduce lipid accumulation by up-regulating the SIRT1-AMPK signaling pathway in HepG2 hepatocarcinoma cells. (PubMed, Mol Biol Rep) - "NOB might be a new therapeutic approach for lipid accumulation management due to inducing the SIRT1-AMPK signaling pathway, however, it requires further investigations."

Journal • Hepatology • Liver Cancer • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology

Strontium Regulating Lipid Metabolism of Bovine Hepatocytes via SIRT1/SREBPs Pathway. (PubMed, J Steroid Biochem Mol Biol) - "Molecular docking indicated that Sr²⁺ binds with high affinity to Asp-481/483 of SIRT1, while SIRT1 inhibition with EX-527 abolished Sr-mediated lipid-lowering effects. Additionally, Sr promoted PPARα nuclear translocation to enhance β-oxidation and upregulated LDLR expression to facilitate lipid efflux. This study elucidated the multi-target molecular mechanism of Sr alleviating lipid metabolism disorders in bovine hepatocytes through the SIRT1/SREBPs pathway, providing a theoretical foundation for the application of Sr in preventing metabolic diseases in dairy cows."

Journal • Dyslipidemia • Metabolic Disorders • FASN • LDLR • PPARA

TRPV4-dependent signaling pathways play essential regulatory roles in high salt-induced cardiac hypertrophy via autophagic alterations. (PubMed, J Cardiovasc Pharmacol) - "Salt-induced autophagic activity was enhanced by inhibiting Class I PI3-Kinase (PI3KC1) with LY294002 or Akt with AZD5363, but got undermined by AMPK inhibition with Compound C (CC) or SIRT1 inhibition with EX-527...Thus, both PI3KC1 and AMPK signaling pathways participate in salt-induced cardiac hypertrophy via shared upstream component of TRPV4: lower salt triggers AMPK, scavenges ROS, preventing cardiac hypertrophy, whilst higher salt activates PI3KC1 with opposite effects. Our findings illuminate potential therapeutic effects of interfering TRP-related channels on high salt-induced hypertrophy and other mechanical stretch force-associated diseases."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Gene Therapies • Heart Failure • Hypertension • Immunology • TRPV4

Apelin-13 enhances neurofunctional recovery and suppresses neuroinflammation via the SIRT1/NF-κB axis in ischemic stroke. (PubMed, Cell Immunol) - "Apelin-13 exerts neuroprotective effects in ischemic stroke by preserving BBB integrity, reducing neuronal apoptosis, and suppressing neuroinflammation. These effects are mediated through SIRT1 activation and NF-κB inhibition. Targeting the Apelin-13/SIRT1/NF-κB axis may offer a promising therapeutic strategy for mitigating neuroinflammation and improving stroke recovery."

Journal • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke • Vascular Neurology • CASP3

THE MECHANISM OF PARP INHIBITOR ENHANCE DECITABINE FUNCTION IN TET2-DEFICIENT MYELOID LEUKEMIA (EHA 2025) - "EX527 reduced the expression of PARP, SIRT1, γ-H2AX, and XRCC1 proteins, as well as SIRT1.The construction of the shTET2 HL60 and K562 stable-transformed cell lines was effective, and compared to the control group, the expression of DNA damage repair proteins including PARP1 and -HA2X was up-regulated. Due to the functional lack of TET2/SIRT1, after decitabine therapy of TET2-deficient myeloid tumors, the DNA repair mechanism in cancer cells activated DNA repair enzymes such PARP1 and XRCC1 instead. Decitabine's pro-apoptotic activity on shTET2 HL60 and K562 cells was therefore increased by PARP inhibitors, which synergistically increased the tumor-killing effect."

Hematological Malignancies • Leukemia • Oncology • CASP3 • H2AX • SIRT1 • TET2 • XRCC1

Human umbilical cord mesenchymal stem cell-derived exosomes repair IBD by activating the SIRT1-FXR pathway in macrophages. (PubMed, Stem Cell Res Ther) - "HucMSC-Ex alleviates IBD by reducing the acetylation level of FXR through activating the SIRT1-FXR pathway in macrophages and directly negatively regulating the activation of NLRP3 inflammasomes, thus inhibiting the occurrence of the inflammatory process."

Journal • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Immunology • Inflammatory Bowel Disease • Leukemia • Oncology • NLRP3

Proanthocyanidins delaying the premature ovarian insufficiency through regulatory sirt1-p53-p21 signaling pathway in female germline stem cells. (PubMed, J Ovarian Res) - "PACS delay premature ovarian insufficiency (POI) through regulating the Sirt1-p53-p21 signaling pathway involving FGSCs."

Journal • Women's Health • CDKN1A • POU5F1

Loganin ameliorates left ventricular fibrosis and dysfunction induced by pressure overload via the Sirt1/AKT/TGF-β1 signaling pathway. (PubMed, J Nat Med) - "Notably, the administration of the Sirt1 inhibitor, EX527, effectively abolished the protective effects of LG. Therefore, the cardio-protective effects of LG were mediated through the activation of the Sirt1/Akt/TGF-β1 signaling pathway, leading to reduced fibrosis and improved cardiac function."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • TGFB1

Icariin attenuates oxidative stress via SIRT1/PGC-1α pathway in SAH mice. (PubMed, Exp Neurol) - "These effects were associated with SIRT1 activation and were reversed by EX527 treatment. In conclusion, this study explored the protective effects of ICA against SAH-induced oxidative damage, suggesting that ICA could be a potential therapeutic agent for SAH."

Journal • Preclinical • Cardiovascular • CNS Disorders • Hematological Disorders • Subarachnoid Hemorrhage

Salidroside impedes Ang II-infused myocardial fibrosis by activating the SIRT1-Nrf2 pathway. (PubMed, Iran J Basic Med Sci) - "Additionally, SAL significantly inhibited atrial fibroblasts, whereas EX527, an inhibitor of SIRT1, noticeably increased the migration ability. Furthermore, SAL suppressed intracellular ROS production and oxidative stress in Ang II-infused atrial fibroblasts. SAL protects against myocardial fibrosis infused by Ang II by activating the SIRT1-Nrf2 pathway."

Journal • Fibrosis • Immunology

Dimethyl Fumarate Improves Non-Alcoholic Fatty Liver Disease by Regulating SIRT1 Signal to Inhibit MAMs Over-Enrichment. (PubMed, Eur J Pharmacol) - "Moreover, the beneficial effects of DMF on oxidative stress, mitochondrial dysfunction, and hepatic steatosis were abrogated by co-administration of EX527, a selective SIRT1 inhibitor. In summary, our findings demonstrate that DMF alleviates mitochondrial Ca2+ dysregulation caused by aberrant MAMs enrichment, thereby reducing oxidative stress and mitochondrial dysfunction, ultimately inhibiting lipid accumulation in hepatocytes. These results provide new insights into the therapeutic potential of DMF for NAFLD treatment."

Journal • Addiction (Opioid and Alcohol) • Hepatology • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease

L-theanine prevents myocardial injury in sleep‑deprived mice by suppressing ferroptosis through SIRT1. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "This study utilized a modified multiple-platform water environment method to establish an SD model and induce a ferroptosis model in H9c2 cells pretreated with erastin. Notably, the SIRT1 inhibitor EX-527 can counteract the protective effect of L-theanine against ferroptosis in cardiomyocytes. These findings highlight that L-theanine mitigates SD-induced cardiac injury primarily by suppressing ferroptosis through SIRT1 in cardiomyocytes."

Journal • Preclinical • Cardiovascular • SIRT1

Protein Kinase C Epsilon Overexpression Protects the Heart Against Doxorubicin-Induced Cardiotoxicity Via Activating SIRT1. (PubMed, Cardiovasc Toxicol) - "Cardiomyocytes in a subgroup were treated with sirtuin-1 (SIRT1) selective inhibitor Ex527. IP study showed that PKC-ε could directly or indirectly bind SIRT1 in cardiomyocytes, and the protect effects of PKC-ε were further canceled by SIRT1 inhibition. In conclusion, activating SIRT1 may represent a major mechanism whereby PKC-ε protects the heart against DOX-induced cell apoptosis and oxidative stress."

IO biomarker • Journal • Cardiovascular • BCL2 • CASP3 • PRKCE • SIRT1

Cordycepin ameliorates morphine tolerance by inhibiting spinal cord ferroptosis and inflammation via targeting SIRT1. (PubMed, Int J Med Sci) - "Further research found that the above effects of cordycepin on morphine-tolerant rats were abolished by SIRT1 selective inhibitor EX-527. Thus, these findings indicated that cordycepin could ameliorate the development of morphine tolerance by inhibiting spinal cord ferroptosis and inflammation via targeting SIRT1. Collectively, these results demonstrated the protective effects of cordycepin and highlighted its therapeutic potential as a drug component for morphine tolerance treatment and prevention."

Journal • Inflammation • GPX4 • IL1B • IL6 • SIRT1 • SLC7A11 • TNFA

Bergenin Alleviates Myocardial Ischemia/Reperfusion Injury via Regulating SIRT1 Through Ferroptosis. (PubMed, J Inflamm Res) - "The in vivo model of myocardial I/R injury was established by transient ligation of the left anterior descending coronary artery in Sprague-Dawley rats, which were divided into sham, I/R, I/R+bergenin, and I/R+bergenin+erastin (an agonist of ferroptosis) groups.After the model was established, the rats underwent echocardiography to assess the cardiac function...EX527, a SIRT1 inhibitor, was used to further explore the role of SIRT1 in the myocardial protection of bergenin...Moreover, Western blotting showed that bergenin activated SIRT1, and increased the phosphorylation of AMPK and the expression level of PGC-1α. Bergenin exerted a protective effect on the myocardium by modulating the ferroptosis process during myocardial I/R injury through the SIRT1/AMPK/PGC-1α pathway."

Journal • Cardiovascular • Metabolic Disorders • Myocardial Ischemia • Reperfusion Injury • SIRT1

NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway. (PubMed, Front Pharmacol) - "Sirt1 dependency was confirmed using inhibitor Ex527...Our findings establish NMN as a multifaceted therapeutic agent that preserves neurocognitive function and intestinal homeostasis in aging models by orchestrating antioxidative, anti-inflammatory, and antiapoptotic responses through Sirt1/AMPK/PGC-1α activation. This work provides translational insights into NAD+-boosting strategies for age-related disorders."

Journal • Preclinical • CNS Disorders • Inflammation • CDKN1A • IL10 • IL1B • IL6 • TNFA

Quercetin alleviates cerebral ischemia and reperfusion injury in hyperglycemic animals by reducing endoplasmic reticulum stress through activating SIRT1. (PubMed, PLoS One) - "In contrast, the SIRT1 selective inhibitor EX-527 blocked the effect of quercetin on protein expression in the SIRT1/PERK pathway and aggravated HT22 cell injury. These findings indicate that quercetin inhibits ERS-mediated apoptosis through modulating the SIRT1 and PERK pathway. In conclusion, quercetin alleviates hyperglycemic CIRI by inhibiting ERS-mediated apoptosis through activating SIRT1 that consequently suppressed ERS signaling."

Journal • Cardiovascular • Diabetes • Reperfusion Injury • ATF4 • ATF6 • HSPA5 • SIRT1

Bergenin promotes mitochondrial biogenesis via the AMPK/SIRT1 axis in hepatocytes. (PubMed, J Med Invest) - "SIRT1 expression was induced in bergenin-treated cells and may be responsible for bergenin-inducible mitochondrial biogenesis, which was abolished by the SIRT1 inhibitor EX-527...Invest. 72 : 66-75, February, 2025."

Journal • Genetic Disorders • Hepatology • Obesity • AMPK

Quaking-cZFP609 Axis Remedies Aberrant Plasticity of Vascular Smooth Muscle Cells via Mediating Platelet-Derived Growth Factor Receptor β Degradation. (PubMed, MedComm (2020)) - "Furthermore, the acetylation of QKI is increased by inhibiting SIRT1 with the selective and potent inhibitor EX527 or deletion of SIRT1, accompanied with parallel decrease in cZFP609 formation...Overexpression of cZFP609 remedies aberrant plasticity and overproliferation of VSMCs, and ameliorates neointimal formation. Together, these results highlight that modulating the QKI-cZFP609 axis may help propel repair without stenosis as a therapeutic strategy in vascular injury."

Journal • PDGFRB

The Role of the Sirt1/Foxo3a Pathway in Mitigating Myocardial Ischemia-Reperfusion Injury by Dexmedetomidine. (PubMed, Chem Biol Drug Des) - "Myocardial ischemia-reperfusion injury (MIRI) significantly affects the prognosis of cardiac surgery patients. These protective effects were markedly reversed by EX527. These findings indicate that Dex alleviates MIRI by restoring Sirt1 expression and activating FoxO3a."

IO biomarker • Journal • Anesthesia • B Cell Lymphoma • Cardiovascular • Lymphoma • Myocardial Infarction • Myocardial Ischemia • Oncology • Reperfusion Injury • BAX • BECN1 • CASP3 • MAP1A

The microglial state transition as a novel mechanism by which fresh Baihe Dihuang decoction prevents depression by regulating SIRT1/HMGB1 signaling. (PubMed, Phytomedicine) - "This study showed that FBD prevents depression by mediating a microglial state transition via the SIRT1/HMGB1 signaling pathway, providing a promising and novel antidepressant therapeutic strategy."

IO biomarker • Journal • CNS Disorders • Depression • Mood Disorders • Oncology • Psychiatry • BAX • BCL2 • CASP3 • HMGB1 • IL1B • IL6 • TNFA

Empagliflozin Plays Vasoprotective Role in Spontaneously Hypertensive Rats via Activation of the SIRT1/AMPK Pathway. (PubMed, Cells) - "The SIRT1 inhibitor (EX527) abolished EMPA's effects on Ach-mediated relaxation and U46619-induced vasoconstriction, while AMPK inhibition reduced Ach-mediated relaxation and Phe-induced vasoconstriction. These properties could improve vascular health in patients with hypertension and related conditions. Further studies are needed to explore new indications for SGLT2 inhibitors."

Journal • Preclinical • Cardiovascular • Hypertension