Cyclic peptide-decorated PtIV-DCA prodrug triggers ferroptosis in glioblastoma via the disruption of energy metabolism.

Glioblastoma (GBM), the most prevalent and aggressive primary malignant tumor of the central nervous system in adults, presents substantial therapeutic challenges due to its aberrant metabolic reprogramming. Integrins, a large family of cell surface receptors, play a pivotal role in the progression of gliomas, and cyclic peptides are known to target these receptors with high affinity and specificity. Herein, a metabolic-interfering PtIV complex DPR was constructed by anchoring a cyclic peptide (RGDfK)c and dichloroacetate (DCA) at the axial positions of cisplatin. DPR exhibited potent and selective cytotoxicity against U87-MG glioblastoma cells with high expression of integrin αvβ3. Mechanistic investigations revealed that DPR suppressed the expression of pyruvate dehydrogenase kinase (PDK), reduced the levels of lactate and ATP, induced mitochondrial DNA (mtDNA) damage, and impaired mitochondrial function, effectively disrupting energy homeostasis in GBM cells. Furthermore, this disruption of energy metabolism triggered ferroptosis, characterized by the accumulation of lipid peroxide (LPO) and malondialdehyde (MDA), the depletion of glutathione (GSH), alteration in mitochondrial morphology and the downregulation of glutathione peroxidase 4 (GPX4). Moreover, DPR demonstrated remarkable anti-angiogenesis activity in addition to its direct anticancer activity. Notably, DPR achieved remarkable antitumor efficacy with minimal systemic toxicity in a GL261-bearing mouse model. This study highlights DPR as a promising GBM-target PtIV complex that exerts therapeutic effects by synergistically interfering with energy metabolism and inducing ferroptosis, providing an innovative strategy to overcome therapeutic resistance in GBM.