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Resveratrol and metformin are cardiometabolic modulators with antioxidative and mitochondrial effects, but their sex-dependent actions in human iPSC-derived endothelial cells (iPSC-EC) remain unclear. iPSC-EC generated from peripheral blood mononuclear cells of six male and six female donors were stimulated with TNF-\u03b1 to induce a pro-atherogenic phenotype and subsequently treated with resveratrol or metformin. Mitochondrial ROS production, mitochondrial content, endothelial permeability, mitochondrial respiration, inflammatory mediators and LDH release were quantified in a sex-stratified manner. In this TNF-\u03b1-driven human iPSC-EC inflammatory dysfunction model, male iPSC-EC displayed stronger mitochondrial superoxide signal, inflammatory activation and endothelial barrier disruption, whereas female iPSC-EC showed a trend towards impaired mitochondrial respiration and reduced IL-10. Resveratrol and metformin trend towards reduced selected TNF-\u03b1 associated endothelial injury markers. Resveratrol and metformin attenuated TNF-\u03b1\u2013associated oxidative stress, cytokine secretion, permeability and LDH release, with male cells mainly benefiting from decreased mitochondrial superoxide signal and inflammation, and female cells showing non-significant tendencies towards improved mitochondrial respiration and restoration of IL-10. These findings highlight cellular sex as a critical determinant of endothelial immunometabolic responses to inflammatory stress and suggest that resveratrol- and metformin-based strategies for vascular protection should be evaluated in a sex-aware manner.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1903774","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T05:32:12Z","timestamp":1786599132000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Sex-specific effects of resveratrol and metformin on mitochondrial function and inflammatory activation in a TNF-\u03b1-driven human iPSC-derived endothelial dysfunction model"],"prefix":"10.3389","volume":"17","author":[{"given":"Julia","family":"Temp","sequence":"first","affiliation":[{"name":"Department of Urology, Eberhard Karls University of Tuebingen","place":["Tuebingen, 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