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

Ginsenoside Rh1 Attenuates Alzheimer's Disease-Like Deficits by Modulating Oxidative Stress and Mitochondrial Dysfunction via SIRT1-Related Signaling. (PubMed, Phytother Res) - "Importantly, the SIRT1 inhibitor EX-527 and SIRT1 knockdown both significantly reversed these protective effects...In conclusion, our findings indicate that ginsenoside Rh1 exerts neuroprotective effects against AD in vivo and in vitro, at least partly through SIRT1-related signaling, which subsequently attenuates oxidative stress and ameliorates mitochondrial dysfunction. These results suggest that Rh1 may represent a promising candidate for further investigation for AD intervention."

Journal • Alzheimer's Disease • CNS Disorders • Metabolic Disorders

Tenghuang Jiangu Capsules promote Treg cell differentiation in rat model of postmenopausal osteoporosis via modulation of SIRT1-mediated JAK3/STAT5 pathway (PubMed, Zhongguo Zhong Yao Za Zhi) - "The successfully modelled rats were randomized into model, positive control(estradiol valerate, 0.09 mg·kg~(-1)), high-dose(0.36 g·kg~(-1)) TJC, medium-dose(0.18 g·kg~(-1)) TJC, low-dose(0.09 g·kg~(-1)) TJC, and SIRT1 inhibitor(EX-527, 1 mg·kg~(-1)) groups(10 per group). Simultaneously, it increased the number of Treg cells in the femoral bone marrow(P<0.01), upregulated the mRNA level of OPG and the protein levels of SIRT1, STAT5, TGF-β, p-JAK3/JAK3, and OPG(P<0.05 or P<0.01), and downregulated the mRNA and protein levels of RANKL(P<0.01) in the femur of PMOP rats. The above results indicated that TJC could maintain bone homeostasis in PMOP rats by promoting Treg cell differentiation via modulation of SIRT1-mediated JAK3/STAT5 pathway."

Journal • Preclinical • Osteoporosis • Rheumatology • FOXP3 • IL10 • JAK3 • STAT5 • TGFB1 • TNFRSF11B • TNFSF11

Adenoviral-Mediated SIRT1 Expression Restores Lung Architecture and Reduces Fibrotic Progression in Experimental Models. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "Pharmacological modulation of SIRT1 was also tested using the activator SRT1720 and the inhibitor EX527. Adenoviral SIRT1 gene delivery exerts protective effects on the alveolar epithelium in vitro and reverses established PF in vivo through epigenetic regulation of key profibrotic pathways. This dual approach highlights the translational potential of SIRT1 as a therapeutic target for PF."

Journal • Fibrosis • Gene Therapies • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • SIRT1

Syringaresinol activates the skeletal muscle SIRT1-FNDC5/irisin axis to enhance weight management. (PubMed, 3 Biotech) - "Differentiated C2C12 myotubes were treated with SYR, the SIRT1 activator SRT1720, and the SIRT1 inhibitor EX-527 to assess Irisin-related readouts, mitochondrial-associated markers, gene expression, and SIRT1/PGC-1α protein abundance. SYR is associated with SIRT1/PGC-1α-related remodeling, Irisin-related readouts, and attenuated HFD-induced weight gain. These findings support SYR as a candidate nutritional modulator of muscle-adipose metabolic communication, while causal in vivo mediation by SIRT1, FNDC5, or Irisin requires further pathway-specific validation."

Journal • PPARG

Resveratrol attenuates LPS/CSE-induced macrophage ferroptosis through activation of the Nrf2-ferroportin axis. (PubMed, Int Immunopharmacol) - "Res suppressed AECOPD partially through activation of Nrf2/FPN signaling and subsequent suppression of macrophage ferroptosis. FPN would be a potential therapeutic target in the treatment of AECOPD."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Infectious Disease • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • IL6 • TNFA

Holistic Regulation of Body-Mind Acupuncture Activates Leptin Receptor-AMPK Signaling to Restore Mitochondrial Homeostasis in Chronic Fatigue Syndrome in vitro and in vivo. (PubMed, Chin J Integr Med) - "HRBM acupuncture exerts therapeutic effects in CFS by activating LepR-AMPK signaling, thereby restoring mitochondrial bioenergetics, enhancing antioxidant defenses, and promoting mitophagy."

Journal • Preclinical • Fatigue • Infectious Disease • Metabolic Disorders • LEP • LEPR

Pharmacological activation of SIRT1 alleviates sepsis-associated acute kidney injury by improving renal mitochondrial energy metabolism. (PubMed, Ren Fail) - "SRT1720 ameliorated renal pathological injury and mitochondrial-related abnormalities, whereas EX-527 worsened these changes. These findings suggest that SIRT1 activation attenuates SA-AKI, at least partly by maintaining renal mitochondrial energy homeostasis."

Journal • Acute Kidney Injury • Infectious Disease • Metabolic Disorders • Nephrology • Renal Disease • Septic Shock • SIRT1

Urolithin A Enhances the Development of Porcine Parthenogenetic Embryos by Promoting Mitochondrial Function and Quantity Through the SIRT1/PGC-1α Signaling Pathway. (PubMed, Microsc Microanal) - "However, the effects of UA were completely abolished by EX-527 cotreatment. These results suggest that UA improves preimplantation embryo development by enhancing mitochondrial function and quantity via the SIRT1/PGC-1α signaling pathway."

Journal • Preclinical

Metformin activates the mitochondrial unfolded protein response via the AMPK/SIRT1 pathway to delay intervertebral disc degeneration. (PubMed, Free Radic Biol Med) - "In a rat needle-puncture model, intradiscal metformin preserved disc height and T2 signal, reduced histological degeneration, and increased matrix and UPRmt-related protein expression; these effects were diminished by EX527. Together, these results suggest that reduced AMPK/SIRT1/UPRmt activity contributes to NP-MSC dysfunction during IDD and that metformin may slow disc degeneration by restoring this mitochondrial stress response."

Journal • AMPK • ATF5 • HSPD1 • SIRT1

Rosemary inhalation improves the behavior and cognition of vascular cognitive impairment rats by regulating SIRT1/mTOR pathway-mediated cell apoptosis and autophagy. (PubMed, Iran J Basic Med Sci) - "However, intervention with EX527 attenuated this protective effect. Rosemary inhalation can improve behavior and cognition in VCI rats by regulating SIRT1/mTOR pathway-mediated cell apoptosis and autophagy."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • CASP3

Shengjiang powder ameliorates gastric mucosal injury through activating SIRT1/FOXO1 anti-oxidative stress. (PubMed, Front Pharmacol) - "EX-527 blocked the restorative effects of SJP on FOXO1 expression and antioxidant enzyme activities. SJP ameliorates gastric mucosal injury and inflammation, potentially through modulation of the SIRT1/FOXO1 axis."

Journal • Gastrointestinal Disorder • Inflammation • FOXO1 • IL6 • PTGS2 • SIRT1 • SOD2 • STAT3 • TFF1

Protocatechualdehyde ameliorates OGD/R-induced endothelial injury via the ROS/miR-29b-3p/SIRT1 regulatory axis. (PubMed, Front Pharmacol) - "The results showed that miR-29b-3p was downregulated in OGD/R-treated HUVECs, an effect that was reversed by PCA and the ROS inhibitor N-acetylcysteine (NAC)...To determine whether SIRT1 acts downstream of miR-29b-3p, we used EX527 (a SIRT1 inhibitor) and found that it attenuated the PCA-mediated upregulation of miR-29b-3p...Additional experiments revealed that NAC suppressed ROS by upregulating miR-29b-3p, leading to increased SIRT1 expression and reduced apoptosis. Collectively, these findings demonstrate that PCA ameliorates OGD/R-induced endothelial injury by promoting autophagy and inhibiting apoptosis via the ROS/miR-29b-3p/SIRT1 regulatory axis."

Journal • Cardiovascular • Reperfusion Injury

Tectorigenin protects against muscle atrophy from in vitro nutrient deprivation and in vivo denervation by activating the AMPK/SIRT1/PGC-1α pathway. (PubMed, Br J Pharmacol) - "TG mitigates denervation-induced muscle atrophy through a multi-mechanistic approach involving activation of the AMPK/SIRT1/PGC-1α axis, enhancement of mitochondrial dynamics and restoration of redox homeostasis. This study identifies TG as a promising candidate for clinical translation in the treatment of neurogenic muscle atrophy."

Journal • Preclinical • Muscular Atrophy • Targeted Protein Degradation

High-throughput fluorescence polarization assay for screening sirtuin inhibitors (ACS-Fall 2026) - "The assay can detect NAD+-independent SIRT1-3 inhibitors, as well as NAD+-dependent inhibitors, such as Ex-527 and TM...Compared to previous assays, the FP assay uses much less SIRT1-3 enzymes, a feature important for high-throughput library screening. We believe that the FP assay developed here will accelerate the discovery and development of SIRT1-3 inhibitors."

CNS Disorders

Inhibition of PARP-1 attenuates osteoarthritis progression by suppressing NF-κB signaling and alleviating chondrocyte senescence. (PubMed, Cell Signal) - "PARP-1 inhibition also alleviated IL-1β-induced NAD+ depletion and chondrocyte senescence, as evidenced by decreased p16 expression and SA-β-gal-positive cells, effects that were partially reversed by the SIRT1 inhibitor EX527...In vivo, intra-articular injection of PARP-1 siRNA in an anterior cruciate ligament transection (ACLT)-induced rat OA model alleviated cartilage degradation, as shown by Safranin O/toluidine blue staining and Mankin scoring. Collectively, these findings demonstrate that PARP-1 inhibition attenuates OA progression by suppressing NF-κB signaling and alleviating chondrocyte senescence, suggesting that PARP-1 represents a potential therapeutic target for OA."

Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology • ADAMTS5 • IL1B • MMP13

Isolinderalactone alleviates hepatic ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress through the SIRT1/IRE1α signaling pathway. (PubMed, Int Immunopharmacol) - "ILL attenuates HIRI by simultaneously elevating SIRT1 expression and activating its deacetylase function, thereby restraining IRE1α-dependent ERS and subsequent hepatic injury. These findings highlight ILL as a promising therapeutic candidate for the management of perioperative HIRI."

Journal • Cardiovascular • Hepatology • Inflammation • Liver Failure • Reperfusion Injury • Transplantation

Nicotinamide promotes lipophagy and cholesterol efflux through the SIRT1-LXRα deacetylation-ABCA1 pathway in vascular smooth muscle cells. (PubMed, Biochem Biophys Res Commun) - "Pharmacological inhibition of SIRT1 with EX527 abolished NAM-induced LXRα deacetylation and ABCA1 upregulation, restoring lipid accumulation and confirming the SIRT1 dependency of this pathway...Altogether, NAM attenuates oxLDL-induced lipid accumulation in VSMCs by activating the SIRT1-LXRα axis, which promotes lipophagy and improves ABCA1-mediated cholesterol efflux. Therefore, targeting the SIRT1-LXRα-lipophagy pathway may represent a promising therapeutic approach for the prevention and treatment of atherosclerosis."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • ABCA1 • PLIN2

Phycocyanobilin Attenuates Oligomerized Amyloid β-Induced Neuronal Senescence Through SIRT1-Associated Mechanisms. (PubMed, Nutrients) - "EX527 partially reversed these protective effects. PCB attenuates Aβ1-42 oligomer-induced neuronal senescence-like alterations, at least partly through SIRT1-associated regulation, supporting its potential as a naturally derived anti-senescent neuroprotective compound for AD-related neuronal aging."

Journal • Alzheimer's Disease • CNS Disorders • CDKN1A • CXCL8 • IL1B • IL6 • SIRT1 • TP53

Tetrahydrocurcumin ameliorates depression-like behaviors in chronic restraint stress mice by modulating neuroinflammation and neurotrophic balance via the SIRT1/NF-κB pathway. (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "THC produces significant antidepressant-like effects in CRS mice likely by activating SIRT1 to suppress NF‑κB-mediated neuroinflammation and restore neurotrophic factor expressions. These findings highlight the SIRT1/NF-κB pathway as a key mechanism mediating the therapeutic effect of THC against depression."

Journal • Preclinical • CNS Disorders • Depression • Inflammation • Mood Disorders • Psychiatry • BDNF • TGFB1 • TNFA

Sirtuin signalling governs calcium homeostasis and mitochondrial function in metabolic syndrome cardiomyocytes. (PubMed, Exp Physiol) - "MetS cardiomyocytes exhibited mitochondrial depolarization, increased reactive oxygen species production, elevated basal cytosolic Ca2+ levels, reduced Ca2+ transient amplitude and decreased sarcoplasmic reticulum Ca2+ content. Notably, pharmacological inhibition of SIRT1 with EX527 in control cardiomyocytes recapitulated key features of the MetS phenotype, whereas SIRT1 activation with SRT1720 restored mitochondrial membrane potential, reduced reactive oxygen species production, improved Ca2+ handling, normalized aberrant phosphorylation of Ca2+-handling proteins and attenuated apoptotic signalling. Collectively, these findings identify SIRT1 as a critical integrator of mitochondrial function and Ca2+ homeostasis during metabolic stress, highlighting sirtuin-dependent pathways as promising therapeutic targets in metabolic cardiomyopathy."

Journal • Cardiomyopathy • Cardiovascular • Metabolic Disorders

Diosmetin alleviates retinal ischemia-reperfusion injury through SIRT1-mediated suppression of oxidative stress, inflammation, and PANoptosis. (PubMed, Immunol Res) - "DIO protects against retinal I/R injury by activating SIRT1/Nrf2 to inhibit oxidative stress, inflammation, and PANoptosis, highlighting its therapeutic potential."

Journal • Cardiovascular • Inflammation • Reperfusion Injury • BAX • CASP3 • IL18 • IL1B • NLRP3 • SIRT1 • TNFA

Sinigrin, a bioactive compound from cruciferous vegetables, ameliorates MASLD by activating AMPK/SIRT1/PGC-1α to enhance fatty acid beta-oxidation. (PubMed, Food Funct) - "The functional importance of AMPK was assessed using the pharmacological AMPK inhibitor Compound C (CC) and shRNA-mediated AMPK knockdown, while the involvement of the SIRT1/PGC-1α axis was further evaluated using the SIRT1 inhibitor EX527...Furthermore, the essential role of AMPK was firmly established by the finding that its pharmacological blockade with CC largely abolished Sinigrin's beneficial effects. Collectively, our findings demonstrate that Sinigrin alleviates MASLD by enhancing fatty acid β-oxidation via the AMPK/SIRT1/PGC-1α axis while concurrently inhibiting ferroptosis through enhancement of Nrf2-mediated antioxidant defense."

Journal • Hepatology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • SIRT1

Repurposing drugs for treating dengue haemorrhagic fever and associated autoimmune diseases. (PubMed, In Silico Pharmacol) - "RAF1 targeting drugs Sorafenib and Regorafenib exhibited the most consistent interaction profile across all computational analyses, followed by the SIRT1-targeting compounds selisistat and resveratrol, which demonstrated moderate but consistent computational support. Also, the methods adopted in this study can guide the repurposing of known drugs to treat other pathogen-associated autoimmune diseases. The online version contains supplementary material available at 10.1007/s40203-026-00699-0."

Journal • Dengue Fever • Immunology • SIRT1

Diosgenin Alleviates Age-Related Sarcopenia by Promoting Satellite Cell Proliferation and Myogenic Differentiation via Activation of the SIRT1/PGC-1α Signaling Pathway. (PubMed, Aging Cell) - "Notably, pharmacological inhibition of SIRT1 with EX527 markedly abrogated the diosgenin-induced effects. Molecular docking and cellular thermal shift assays further confirmed the direct interaction between diosgenin and SIRT1. Collectively, these findings demonstrate that diosgenin alleviates age-related sarcopenia by activating the SIRT1/PGC-1α signaling pathway to promote satellite cell proliferation and myogenic differentiation, highlighting its potential as a promising therapeutic candidate for sarcopenia."

Journal • Sarcopenia • IGF1 • PAX7

Sodium Danshensu alleviates oxidative stress-induced endothelial apoptosis and senescence by modulating the SIRT1/p53 pathway. (PubMed, J Ethnopharmacol) - "SDSS alleviates oxidative stress-induced vascular injury and endothelial dysfunction, and that these protective effects are associated with activation of the SIRT1/p53 pathway. These results offer preliminary correlative evidence supporting the traditional use of Danshen in cardiovascular protection, and suggest that SDSS warrants further investigation as a candidate for oxidative stress-associated vascular dysfunction."

IO biomarker • Journal • Cardiovascular • BCL2 • CDKN1A