Peroxisome proliferator-activated receptor gamma (PPARγ) as a mechano-metabolic transducer: coordinating lipid homeostasis through mechanical cues.

The pathogenesis of prevalent metabolic diseases such as obesity, atherosclerosis, metabolic dysfunction-associated steatotic liver disease, and diabetes is intricately linked to dysregulated lipid metabolism. Peroxisome proliferator-activated receptor gamma (PPARγ) is a key transcriptional regulator of lipid homeostasis and a well‑researched therapeutic target. Although biochemical signaling pathways have been the traditional focus, recent studies now highlight the mechanical microenvironment (matrix stiffness, fluid shear stress, and tensile strain) as a pivotal physical metabolism regulator. However, how mechanical signals integrate with PPARγ to control lipid metabolism across tissues and diseases remains poorly defined. This review details the molecular mechanisms by which mechanical cues influence PPARγ expression, activity, and post‑translational modifications, focusing on Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4)-mediated ubiquitination, and protein kinase Cα (PKCα)-extracellular signal-regulated kinase (ERK) pathways. We further explore the critical role of PPARγ in mechano‑metabolic coupling in adipose tissue, liver, and vasculature. Under normal physiological conditions, mechanical loading suppresses PPARγ to promote osteogenesis and vascular homeostasis; under pathological conditions, aberrant signals and PPARγ dysfunction establish a vicious cycle of "mechanical imbalance-metabolic disorder-tissue remodeling." This review suggests that PPARγ may function as a mechano‑metabolic downstream transcriptional transducer linking the mechanical microenvironment to metabolic reprogramming, thereby offering a novel theoretical framework and translational perspective for the physical intervention and targeted therapy of common metabolic diseases.