Novel perspectives on PPARγ regulation: from SPPARMs to the emerging role of lncRNAs in metabolic disorders.

Metabolic disorders-particularly obesity and type 2 diabetes mellitus (T2DM)-have reached pandemic proportions and represent one of the most pressing global health challenges of the 21st century. Peroxisome proliferator-activated receptor gamma (PPARγ) serves as a master regulator of lipid metabolism, insulin sensitivity, and adipocyte differentiation, making it a validated therapeutic target. However, classical thiazolidinediones (TZDs) targeting PPARγ are limited by significant adverse effects including weight gain, fluid retention, and cardiovascular risks. This review systematically examines the structure-function relationships of PPARγ and its multi-layered regulatory mechanisms in metabolic homeostasis. We particularly focus on selective PPARγ modulators (SPPARMs) that target Ser273 phosphorylation-a strategy that preserves insulin-sensitizing efficacy while circumventing TZD-associated toxicities. Notably, we provide the first comprehensive integration of the lncRNA Snhg9 into the PPARγ regulatory framework; the Snhg9-CCAR2-SIRT1-PPARγ axis represents a novel lncRNA-mediated mechanism with potential implications for RNA-based therapeutics. Finally, we propose the DNA-binding domain (DBD) as an emerging target that may enable gene-selective PPARγ modulation-a paradigm shift beyond conventional ligand-binding domain (LBD)-focused strategies. This review provides a strategic roadmap for next-generation PPARγ-targeted therapies in metabolic diseases.