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TITLE: “Synthesis and characterization of Peroxisome Proliferated Activated Receptor (PPAR)-δ Agonists as Promising Treatment for MAFLD”
ABSTRACT: The global rise in metabolic dysfunction-associated liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), represents a major public health challenge worldwide. MASLD is strongly associated with obesity, insulin resistance, mitochondrial dysfunction, and dyslipidemia; creating an urgent need for effective therapeutic strategies. Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors within the nuclear hormone receptor superfamily that regulate lipid and glucose metabolism. Among these, PPAR δ which is ubiquitously expressed and plays a critical role in promoting fatty acid β-oxidation. Selective activation of PPAR δ offers therapeutic advantages by enhancing systemic lipid catabolism without the adverse effects often associated with PPAR γ modulation. In this study, we designed and synthesized thiazolidinedione-based derivatives predicted to exhibit high PPAR δ selectivity using computational modeling with Molecular Operating Environment (MOE). Preliminary molecular modeling and docking analyses identified PPARδ agonists that bind specifically to the activation function 2 (AF-2) ligand binding domain (LBD) of human PPAR receptors, with a particular affinity for the δ subtype. These agonists exhibit selective amino acid interactions that enhance binding affinity while minimizing adverse effects linked to PPARγ activation. Subsequent in vitro analyses using HepG2 liver hepatoma cells confirmed PPARδ activation by protein expression, reduced lipid accumulation by oil-red-o staining, and upregulated key enzymes involved in fatty acid metabolism. Collectively, these findings highlight promising therapeutic candidates for MASLD and metabolic dysfunction-associated steatohepatitis (MASH), warranting further in vivo validation and receptor profiling.
BIO: Dr. Ward completed her undergraduate degree work in chemistry and biology from the University of Michigan before advancing to Wayne State University and attaining a Ph.D. in Medicinal Chemistry. She has an active research laboratory at Ferris State University specializing in Alzheimer’s Disease and Fatty Liver Disease research. She has been a professor in the Doctor of Pharmacy (Pharm.D.) program for the past 24 years and recently authored a textbook this past year entitled Medical Biochemistry and Drug Interaction Basics with Great River Learning publishing company. She is an expert ambassador for holistic online platform awearmarket.com and founder of a high-end herbal and nutritional supplement company called Dr Wards Blends as she has helped many people with pharmacognosy and natural medicine.
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