endurobol (GW501516) / Ligand, GSK - LARVOL DELTA

PPARβ/δ priming enhances mesenchymal stromal cell anti-apoptotic properties on chondrocytes via ANGPTL4 and improves their therapeutic effects in osteoarthritis. (PubMed, Stem Cells Transl Med) - "PPARβ/δ priming enhances the therapeutic potential of MSCs by increasing their resistance to oxidative stress and anti-apoptotic effects on chondrocytes, mediated by ANGPTL4. These findings suggest a promising strategy for optimizing MSC-based therapies for OA."

Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology

Peroxisome Proliferator-Activated Receptor Delta Regulates Myogenic Differentiation via Lipid Droplet-Associated Metabolic Remodeling and p38 MAPK Signaling. (PubMed, Anim Sci J) - "C2C12 myoblasts were induced to differentiate and treated with the PPARδ agonist GW501516 or antagonist GSK3787...These findings demonstrate that PPARδ promotes myogenic differentiation through coordinated lipid metabolic remodeling and p38 MAPK signaling, highlighting an association between metabolic regulation and muscle differentiation. This pathway may represent a potential target for improving muscle development and meat quality in livestock."

Journal • Metabolic Disorders • PLIN2

A magnetic-acoustic dual-fesponsive nanoplatform for targeted PPARδ activation attenuates adolescent idiopathic scoliosis progression. (PubMed, J Nanobiotechnology) - "To overcome the systemic toxicity and hydrophobicity of PPARδ agonists, we developed a magnetic-acoustic dual-responsive nanodelivery system (LIP@PFP/GW/SPIO) for targeted delivery of the PPARδ agonist GW501516. In a bipedal AIS mouse model, this targeted intervention effectively restored mitochondrial function and muscle fiber composition, thereby retarding scoliosis progression. Overall, our findings reveal a metabolic mechanism of AIS pathogenesis and demonstrate a potential targeted therapeutic strategy for its management."

Journal • Fibrosis • Immunology • Metabolic Disorders

Peroxisome proliferator-activated receptor delta loss reduces alloreactive CD4 T cell proliferation and lessens graft-versus-host-disease severity (IMMUNOLOGY 2026) - "Then, we created a T cell conditional PPARδ knockout (KO) mouse strain to supply donor T cells for our GVHD model. We found that GW501516-treated T cells stimulated by MLR had increased transcript levels of FAO genes: a 2-fold increase in acetyl-CoA acyltransferase 2 (Acaa2), a 4-fold increase in perilipin-2 (Plin2) in CD8 T cells as well as a 6-fold (Acaa2) and an 8-fold (Plin2) increase in CD4 T cells (multiple t-test, p=0.01)... These data overall indicate that the loss of PPARδ impairs the ability of donor T cells to infiltrate target organs during GVHD progression."

Graft versus Host Disease • Immunology • CD4 • CD8 • PLIN2

THE ROLE OF PPARδ IN LIPID DROPLET ACCUMULATION IN MICROGLIA (WRMC 2026) - "PPARδ agonism with GW501516 effectively reduces OA-induced lipid droplet accumulation in microglial cells, supporting a regulatory role for PPARδ in microglial lipid metabolism. These results suggest that pharmacologic activation of PPARδ could mitigate the pro-inflammatory, lipid-laden microglial phenotype observed in AD and represents a promising therapeutic avenue. Future studies should validate these findings in APOE4 or human iPSC-derived microglial models and examine additional lipid droplet characteristics such as size, number, and density to further clarify PPARδ's functional impact."

Alzheimer's Disease • CNS Disorders • Metabolic Disorders • ANGPTL4 • GAPDH

Investigation of exercise-mimetic bioactive molecules as modulators of MMP activity and expression in cancer cells. (PubMed, J Enzyme Inhib Med Chem) - "In this study, the possible anti-cancer and anti-metastatic-related effects of six selected exercise mimetics (i.e., AICAR, Icariin, Berberine, Betaine, GW501516, and Metformin) were investigated by targeting activity and/or expression of MMP-2/9 in in vitro model. Among the exercise mimetics, Icariin and Berberine have relatively stronger effects on both the activity of MMP-2 and the expression of MMP-2/9 in cancer cells. These findings highlight the novel potential of exercise mimetics as targeted cancer therapeutics through the regulation of MMP activity and expression in cancer progression and metastasis."

Journal • Lung Cancer • Oncology • Solid Tumor • MMP2 • MMP9

PPARβ/δ contributes to the antidiabetic effect and the increase in GDF15 caused by metformin. (PubMed, Acta Pharmacol Sin) - "Furthermore, treatment of mice with a PPARβ/δ activator, GW501516 (3 mg· kg-1 ·d-1, i.g., for 7 days), increased the levels of these proteins in the kidneys and liver. In contrast, a PPARβ/δ antagonist GSK0660 (50 µM) prevented the increase in GDF15, β-arrestin 1, and PCSK6 levels caused by metformin in cultured podocytes. Collectively, these data uncover a regulatory axis wherein metformin, via PPARβ/δ, orchestrates glucose tolerance, AMPK activity, and GDF15 maturation."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • GDF15 • PCSK6

Investigating the Role of PPAR Delta in Alloreactive T Cells (ASH 2024) - "Culturing agonist-treated cells with 3H-palmitate demonstrated an increase in 3H2O production that was inhibitable by etomoxir, confirming a GW501516-driven increase in FAO in allogenically-stimulated cells. Thus, alloreactive CD8 donor T cells appear to adapt to loss of PPARδ through the upregulation of glutamine metabolism and an increased reliance on metabolid fuels provide through the panthothenate pathway. Future work will interrogate the vitamin B5/CoA axis in PPARδ KO alloreactive CD8 T and examine potential upstream influence by AMPK and mTOR, the two primary energy regulators of T cells, with the long-term goal of pinpointing therapeutic targets in reducing GVHD."

Bone Marrow Transplantation • Graft versus Host Disease • Immunology • AMPK • CD4 • CD8 • CPT1A • PLIN2

GLP-1 receptor agonist protects glucose-stimulated insulin secretion in pancreatic β-cells against lipotoxicity via PPARδ/UCP2 pathway. (PubMed, Cell Mol Life Sci) - "C57BL/6J mice fed a high-fat diet (HFD) for 12 weeks were treated with exenatide (Exe), GW501516 (GW, a PPARδ agonist), saline, or dimethyl sulfoxide (DM) for 8 weeks, followed by phenotypic assessments. Moreover, Ex-4 failed to reverse mitochondrial function or GSIS in pancreatic β-cells with UCP2 overexpression despite an increase in PPARδ expression. Thus, GLP-1RA Exe/Ex-4 preserved GSIS against lipotoxicity in pancreatic β-cells by modulating mitochondrial function through the PPARδ/UCP2 axis."

Journal

Fatty acid metabolism suppresses neonatal cardiomyocyte proliferation by increasing PDK4 and HMGCS2 expression through PPARδ. (PubMed, PLoS One) - "GW501516, a peroxisome proliferator-activated receptor δ (PPARδ) activator, also upregulated fatty acid metabolism genes and disturbed NRCM proliferation, whereas GSK3787, a PPARδ inhibitor, recovered FA-induced the cell cycle arrest. Furthermore, overexpression of PDK4 or HMGCS2 using a lentiviral vector suppressed cell cycle activity in NRCMs, and silencing either gene regained cell cycle even in FA-rich condition. In conclusion, fatty acid metabolism increased PDK4 and HMGCS2 via PPARδ activation and suppressed NRCM proliferation."

Journal • HMGCS2 • PDK4

Novel Solid Forms of Cardarine/GW501516 and Their Characterization by X-Ray Diffraction, Thermal, Computational, FTIR, and UV Analysis. (PubMed, Pharmaceutics) - "Further investigations have been conducted by powder X-ray diffraction, DTA/TGA thermal analysis, and FTIR spectroscopy. The stability and solubility were analyzed as well."

Journal • Cardiovascular • Dyslipidemia • Metabolic Disorders

GW501516 facilitated tumor immune escape by inhibiting phagocytosis. (PubMed, Eur J Pharmacol) - "In vivo implanted tumor models demonstrated that GW501516 facilitated tumor immune escape, whereas PPARδ loss reversed this effect. Collectively, these findings suggest that GW501516 activates PPARδ to promote colon tumor immune escape via CD47 upregulation."

Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • CD47 • SIRPA

PPARβ/δ upregulates the insulin receptor β subunit in skeletal muscle by reducing lysosomal activity and EphB4 levels. (PubMed, Cell Commun Signal) - "Overall, these findings reveal that PPARβ/δ activation increases InsRβ levels by alleviating ER stress and lysosomal degradation."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • EPHB4 • IR

Fatty acids disturb cardiomyocyte proliferation by increasing PDK4 and HMGCS2 via PPARδ activation (AHA 2024) - "GW501516, a peroxisome proliferator-activated receptor δ (PPARδ) agonist, also increased fatty acid metabolism factors with the reduction of Ki67 positive cardiomyocytes, whereas fenofibrate, a PPARα agonist, or pioglitazone, a PPARγ agonist, caused little or no change in these phenotypes. Fatty acids disturbed NRCM proliferation by upregulating PDK4 and HMGCS2 through the activation of PPARδ independently from β-oxidation."

Heart Failure • Metabolic Disorders • HMGCS2 • PDK4 • PPARA

Peroxisome proliferator-activated receptor δ suppresses the cytotoxicity of CD8+ T cells by inhibiting RelA DNA binding activity. (PubMed, Cancer Res Commun) - "Treatment of ApcMin/+ mice with the PPAR-δ agonist GW501516 reduced the activation of normal and tumor-associated intestinal CD8+ T cells and increased intestinal adenoma burden...Mechanistically, we found that PPAR-δ binds to RelA, interfering with RelA-p50 heterodimer formation in the nucleus, thereby inhibiting its DNA binding in CTLs. Thus, PPAR-δ is a critical regulator of CTL effector function."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • GZMB • IFNG • PPARA

PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells. (PubMed, Biomed Pharmacother) - "Likewise, GW501516 attenuated the phosphorylation of the main downstream intracellular protein target of TGF-β1, suppressor of mothers against decapentaplegic (SMAD)3, as well as the levels of the SMAD3 co-activator p300 via the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) in LX-2 cells. Overall, these findings uncover a new mechanism by which the activation of AMPK by a PPARβ/δ agonist reduces TGF-β1-mediated activation of HSCs and fibrosis via the reduction of both SMAD3 phosphorylation and p300 levels."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • AMPK • COL1A1 • SMAD3 • SMAD4 • TGFB1

Exenatide Activates PPARd to Promote Mitochondrial Function for Insulin Secretion in Islet ß-Cells (ADA 2024) - "However, related molecular mechanisms remain to be further explored. C57BL/6J mice were treated with exenatide, GW501516 (GW, a PPARδ agonist) or saline for 8 weeks after a 12-week high-fat diet (HFD) challenge. Exenatide protects GSIS function in islet β cells by enhancing mitochondrial function through promoting PPARδ expression."

Metabolic Disorders

ACTIVATION OF PPARΔ IN BONE MARROW ENDOTHELIAL PROGENITOR CELLS REPAIRS THEIR HEMATOPOIESIS-SUPPORTING ABILITY AFTER MYELOSUPPRESSIVE INJURY (EHA 2024) - "GW501516, an agonist of PPARδ, repaired the damagedBM EPCs triggered by 5-fluorouracil (5FU) in vitro. The current work provides the first evidence that insufficient level of PPARδ contributes to BM EPC dysfunction,whereas activation of PPARδ in BM EPCs repairs their hematopoiesis-supporting ability after myelosuppressivetherapy, which may provide a potential therapeutic target not only for patients with leukemia, but also forthose with other cancers."

Acute Myelogenous Leukemia • Anemia • Aplastic Anemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Thrombocytopenia • Thrombocytopenic Purpura • Transplantation

Five Novel Polymorphs of Cardarine/GW501516 and Their Characterization by X-ray Diffraction, Computational Methods, Thermal Analysis and a Pharmaceutical Perspective. (PubMed, Pharmaceutics) - "The polymorphs were further investigated by thermal DSC analysis and X-ray diffraction on powders. From a pharmaceutical perspective, the stability and solubility of the polymorphs were analyzed as well."

Journal • Cardiovascular • Metabolic Disorders

Estradiol contributes to sex differences in resilience to septic-induced metabolic dysregulation and dysfunction in the heart via GPER-1-mediated PPARδ/NLRP3 signaling. (PubMed, Metabolism) - "Our findings collectively illuminate the sex-specific cardiac mechanisms influencing septic mortality, offering insights into physiological and pathological dimensions. From a pharmacological standpoint, this study introduces specific GPER-1 activation as a promising therapeutic intervention for males under septic conditions. These discoveries advance our understanding of the sex differences in septic-induced cardiac dysfunction and also present a novel avenue for targeted interventions with potential translational impact."

Journal • Infectious Disease • Metabolic Disorders • Septic Shock • GPER1 • NLRP3

Activation of PPARδ in bone marrow endothelial progenitor cells improves their hematopoiesis-supporting ability after myelosuppressive injury. (PubMed, Cancer Lett) - "Moreover, GW501516, an agonist of PPARδ, repaired the damaged BM EPCs triggered by 5-fluorouracil (5FU) in vitro and in vivo. Mechanistically, we found that increased expression of NADPH oxidases (NOXs), the main ROS-generating enzymes, may lead to elevated ROS level in BM EPCs, and insufficient PPARδ may trigger BM EPC damage via ROS/p53 pathway. Collectively, we found that defective PPARδ contributes to BM EPC dysfunction, whereas activation of PPARδ in BM EPCs improves their hematopoiesis-supporting ability after myelosuppressive therapy, which may provide a potential therapeutic target not only for patients with leukemia but also for those with other cancers."

Journal • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

GW501516-Mediated Targeting of Tetraspanin 15 Regulates ADAM10-Dependent N-Cadherin Cleavage in Invasive Bladder Cancer Cells. (PubMed, Cells) - "By targeting Tspan15 to block ADAM10 activity on N-cadherin, GW501516 could prevent NTF pro-tumoral effects and be a promising molecule to treat bladder cancer. More interestingly, it could optimize the effects of the N-cadherin antagonists those such as ADH-1 that target the N-cadherin ectodomain."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • ADAM10 • CDH2 • CEBPZ

The role of PPARδ in murine T cell activation (IMMUNOLOGY 2024) - "To understand PPARδ's impact on FAO in T cells, we stimulated naïve T cells with F1 splenocytes (in a mixed leukocyte reaction (MLR)) in the presence of the PPARδ agonist GW501516...Together, these data imply that PPARδ both drives FAO and mediates anti-inflammatory actions in T cells responding to an allogeneic stimulus. The intersectional role of PPARδ in metabolism and inflammation requires nuanced consideration, particularly regarding its therapeutic potential in modulating T-cell mediated immune responses."

Preclinical • Graft versus Host Disease • Immunology • Oncology • Transplantation • CD4 • CD8 • TNFA

PPARβ/δ-ANGPTL4 axis mediates the promotion of mono-2-ethylhexyl phthalic acid on MYCN-amplified neuroblastoma development. (PubMed, Sci Total Environ) - "Because MEHP can bind to the PPARβ/δ protein and initiate the expression of the downstream gene angiopoietin-like 4 (ANGPTL4), the PPARβ/δ-specific agonist GW501516 and antagonist GSK3787, the recombinant human ANGPTL4 protein, and the knockdown of gene expression confirmed the regulation of the PPARβ/δ-ANGPTL4 axis on the malignant phenotype of neuroblastoma...We have demonstrated for the first time that MEHP can target binding to PPARβ/δ and affect the progression of neuroblastoma by activating the PPARβ/δ-ANGPTL4 axis. This mechanism confirms the health risks of plasticizers as tumor promoters and provides new data support for targeted prevention and treatment of neuroblastoma."

Journal • CNS Tumor • Metabolic Disorders • Neuroblastoma • Oncology • Solid Tumor • MYCN

Inhibitory Effect of PPARδ Agonist GW501516 on Proliferation of Hypoxia-induced Pulmonary Arterial Smooth Muscle Cells by Regulating the mTOR Pathway. (PubMed, Curr Med Sci) - "GW501516 inhibited the proliferation of PASMCs induced by hypoxia through blocking the mTOR/Skp2/p27 signaling pathway."

Journal • SKP2