Recent advances and therapeutic applications of PPARγ-targeted ligands based on the inhibition mechanism of Ser273 phosphorylation.

PPARγ functions as a master ligand-dependent transcription factor that regulates the expressions of a variety of key genes related to metabolic homeostasis and inflammatory immunity. It has been recognized as a popular and druggable target in modern drug discovery. Similar to other nuclear receptors, PPARγ is a phosphoprotein, and its biological functions are regulated by phosphorylation, especially at Ser273 site which is mediated by CDK5 or ERK. In the past decade, the excessive level of PPARγ-Ser273 phosphorylation has been confirmed to be a crucial factor in promoting the occurrence and development of some major diseases. Ligands capable of inhibiting PPARγ-Ser273 phosphorylation have shown great potentials for treatment. Despite these achievements, to our knowledge, no related review focusing on this topic has been conducted so far. Therefore, we herein summarize the basic knowledge of PPARγ and CDK5/ERK-mediated PPARγ-Ser273 phosphorylation as well as its physiopathological role in representative diseases. We also review the developments and therapeutic applications of PPARγ-targeted ligands based on this mechanism. Finally, we suggest several directions for future investigations. We expect that this review can evoke more inspiration of scientific communities, ultimately facilitating the promotion of the PPARγ-Ser273 phosphorylation-involved mechanism as a promising breakthrough point for addressing the clinical treatment of human diseases.