A Cyclometalated Iridium(III) Complex Exerts High Anticancer Efficacy via Fatty Acid Beta-Oxidation Inhibition and Sphingolipid Metabolism Reprogramming

Given the extensive role of lipids in cancer development, there is substantial clinical interest in developing therapies that target lipid metabolism. In this study, we identified one cyclometalated iridium complex (<b>Ir2</b>) that exhibits potent antiproliferation activity in MIA PaCa-2 cells by regulating fatty acid metabolism and sphingolipid metabolism simultaneously. <b>Ir2</b> also efficiently overcomes cisplatin resistance <i>in vitro</i>. Satisfyingly, the generated Ir2@F127 carriers, as a temperature-sensitiv<i>e in situ</i> gelling system of <b>Ir2</b>, showed effective cancer treatment with minimal side effects in an <i>in vivo</i> xenograft study. To the best of our knowledge, <b>Ir2</b> is the first reported cyclometalated iridium complex that exerts anticancer activity in MIA PaCa-2 cells by intervening in lipid metabolism, which provides an alternative pathway for the anticancer mechanism of cyclometalated iridium complexes.