Background <p>Retroperitoneal liposarcoma (RLPS) is characterized by high heterogeneity, frequent recurrence and dismal prognosis. Surgery remains the main therapeutic strategy, while no effective targeted therapy is available for advanced RLPS. Peroxisome proliferator-activated receptor γ (PPARγ) is a core regulator of adipocyte differentiation, yet its function and regulatory mechanisms in RLPS remain unclear.</p> Methods <p>Eighty clinical specimens and information from RLPS patients were collected and analyzed to examine PPARγ expression and assess its prognostic value, integrated with results from multi-database. The biological functions of PPARγ were investigated by constructing viral vectors for its overexpression and knockdown in both in vivo and in vitro. Bioinformatic analysis, multiplex immunofluorescence, co-immunoprecipitation and multiple approaches were applied to elucidate PPARγ-mediated mechanisms and its crosstalk with the downstream PI3K/AKT cascade. The anti‑tumor activity and biosafety of the PPARγ agonist troglitazone (TGZ) were assessed in vitro and in RLPS Cell Line-Derived/Patient-Derived Xenograft models.</p> Results <p>PPARγ was significantly downregulated in RLPS tissues and acted as an independent prognostic predictor. Overexpression of PPARγ inhibited malignant phenotypes and promoted apoptosis of RLPS cells, whereas PPARγ knockdown exerted the opposite effects. Mechanistically, PPARγ directly bound to PI3K and exerted tumor‑suppressive functions by suppressing the phosphorylation and activation of the PI3K/AKT pathway. TGZ upregulated PPARγ expression, regulated the PI3K/AKT pathway in vitro, and exhibited robust antitumor activity alongside favorable biosafety in vivo.</p> Conclusions <p>PPARγ exerts antitumor effects via inactivation of the PI3K/AKT signaling pathway and serves as an independent prognostic biomarker in RLPS. The PPARγ agonist TGZ holds great potential as an antitumor drug candidate for RLPS.</p> Graphical Abstract <p></p>