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Natural products, known for their diverse chemical structures and mechanisms of action, offer promising anti\u2010tumor potential with favorable safety profiles and lower toxicity compared to synthetic drugs. 2\u2010Undecanone, a natural compound extracted from <jats:italic>Houttuynia cordata<\/jats:italic> Thunb., has demonstrated anti\u2010tumor effects, but its specific role in RCC treatment remains unclear. In this study, we integrated network pharmacology with in vitro experiments to explore the mechanisms underlying 2\u2010Undecanone's effects on RCC. Our results reveal that 2\u2010Undecanone effectively inhibits RCC cell viability, proliferation, and migration. Mechanistically, we discovered that 2\u2010Undecanone induces ferroptosis in RCC cells by promoting reactive oxygen species (ROS) generation, intracellular Fe<jats:sup>2+<\/jats:sup> accumulation, glutathione (GSH) production, lipid peroxidation, and modulation of the STAT3\/GPX4 signaling pathway. Furthermore, 2\u2010Undecanone lowers the IC50 value of sunitinib in RCC cells, enhancing their sensitivity to this targeted therapy. Additionally, 2\u2010Undecanone potentiates sunitinib\u2010induced ferroptosis. In summary, our research reveals that 2\u2010Undecanone enhances the sensitivity of RCC cells to sunitinib through targeting the STAT3\/GPX4 pathway, providing new insights into potential therapeutic strategies for RCC.<\/jats:p>","DOI":"10.1002\/biof.70016","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T03:23:50Z","timestamp":1744169030000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["2\u2010Undecanone induces ferroptosis via the <scp>STAT3<\/scp>\/<scp>GPX4<\/scp> pathway to enhance sensitivity of renal cell carcinoma to sunitinib"],"prefix":"10.1002","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8505-0733","authenticated-orcid":false,"given":"Zixuan","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Urology Tongren Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 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