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Peroxisome proliferator-activated receptor gamma (PPAR\u03b3) is a key transcriptional regulator of lipid homeostasis and a well\u2011researched 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 PPAR\u03b3 to control lipid metabolism across tissues and diseases remains poorly defined. This review details the molecular mechanisms by which mechanical cues influence PPAR\u03b3 expression, activity, and post\u2011translational 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 C\u03b1 (PKC\u03b1)-extracellular signal-regulated kinase (ERK) pathways. We further explore the critical role of PPAR\u03b3 in mechano\u2011metabolic coupling in adipose tissue, liver, and vasculature. Under normal physiological conditions, mechanical loading suppresses PPAR\u03b3 to promote osteogenesis and vascular homeostasis; under pathological conditions, aberrant signals and PPAR\u03b3 dysfunction establish a vicious cycle of \u201cmechanical imbalance\u2013metabolic disorder\u2013tissue remodeling.\u201d This review suggests that PPAR\u03b3 may function as a mechano\u2011metabolic 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.<\/jats:p>","DOI":"10.1186\/s43556-026-00544-y","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T09:53:01Z","timestamp":1786528381000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Peroxisome proliferator-activated receptor gamma (PPAR\u03b3) as a mechano-metabolic transducer: coordinating lipid homeostasis through mechanical cues"],"prefix":"10.1186","volume":"7","author":[{"given":"Ming-Yue","family":"Zhong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Ya","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Hui","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Kang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2659-9221","authenticated-orcid":false,"given":"Jun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"issue":"16","key":"544_CR1","doi-asserted-by":"publisher","first-page":"3193","DOI":"10.2174\/0929867327666200716113136","volume":"28","author":"S Mal","year":"2021","unstructured":"Mal S, Dwivedi AR, Kumar V, Kumar N, Kumar B, Kumar V. 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