When activated, these receptors can act as lipometabolic sensors, which can also significantly alter metabolic processes [19]. Their impact in metabolic processes takes place by a gene transcription procedure, which is identical for all PPARs [19]. PPAR stimulation requires exogenous (dietary) and endogenous binding compounds or PPAR ligands that can penetrate the cytoplasm and nuclear membranes to access the PPARs [20]. Throughout the above procedure, small soluble proteins such as fatty acid binding proteins (FABPs) might be implicated in enhancing cellular and nuclear transport. PPARs are also heterodimer by the retinoic \(X\)\(\alpha\) receptor (RXR-a) [21]. When there is no PPAR ligand, the PPAR-RXR heterodimer binds to compressor protein complexes, which can subsequently negatively regulate gene expression [22]. PPARs include specific N-terminal activation sites, central greatly conserved DNA-binding sites, and C-terminal ligand-binding domains (LBDs). The agonist/antagonist binding regions of PPAR isotypes show almost seventy percent sequence identity, allowing them to bind to natural fatty acids that transfer into a locus in the LBD and thereby activate them [23]. In general, hydrophobic and hydrogen-bonding interactions may contribute to stabilizing the binding of a potential ligand to PPARs [24; 25]. Thus, as mentioned above, concerning the chemical space covered by PPAR ligands, there is high demand regarding the LBD in terms of both lipophilicity and molecular mass [7; 10]. PPARs modulate genes' expression pertaining to many cell procedures, such as glucose metabolism, mitochondrial genesis, insulin action, cell proliferation, fat oxidation, inflammation, cell differentiation, and consequently cell survival [26]. PPAR expression has also been reported in the cardiovascular and immune systems, and especially in the innermost layer (tunica intima) and the middle layer (tunica media) of the vascular cells as well as in the lymphocytes, dendritic cells, and macrophages, respectively. PPARs can also suppress the synthesis of cytokines (e.g., interleukin-9 and IL-6) and pro-inflammatory intermediates [27]. Throughout the activation of the ligands, PPARs are capable of inhibiting pro-inflammatory genes' expression to exert anti-inflammatory properties by intervening in the binding of transcription molecules, such as nuclear factor kappa B (NF-kB) to DNA [27; 28]. Moreover, several PPAR agonists can induce endothelial nitric oxide synthase (NOS) activation by various pathways, which ameliorates vascular endothelial disorder through enhancing the endothelial bioavailability of nitric oxide (NO) and providing oxidative stress prevention [5; 29; 30]. PPARs have exhibited a broad bioactivity range by behaving as regulators or mediators in multiple metabolic pathways [29; 30; 31]. Therefore, they could become a target of pharmacological technology for the treatment of metabolic disorders and non-communicable diseases as well as cancer [29; 30; 31]. Although synthetic PPAR agonists such as thiazolinedones and fibrates have been aspects of dyslipidemia and/or hyperglycemia treatment, serious side effects like bone fractures, myopathy, and increasing body weight as well as fluid retention contribute to natural compounds attracting the interest of medicine research and technology [29; 30; 31]. Notably, although PPARs have several similar actions, they also exert different effects, which are ascribed to their different expression locations in diverse tissues, sensitivities to ligands, and modulation of target genes [32]. More to the point, the PPAR LBD contains 12 \(\alpha\)-helices, which establish the typical three-layer antiparallel \(\alpha\)-helical sandwich with a small four-stranded sheet. The above structure outlines a bulky Y-shape hydrophobic region, with a ligand-binding cavity that is broader regarding PPARs compared to the other receptors [33; 34].