l-Cysteine-Triggered Regulation of the Mitochondrial Energy Metabolism To Enhance Chemotherapy of Triple-Negative Breast Cancer

Although cisplatin has widely been used for treating triple-negative breast cancer (TNBC), its anticancer effect remains unsatisfactory, due to the heavy resistance. In this study, oxidative phosphorylation (OxPhos) was proposed to effectively regulate the intracellular energy metabolism of heat and adenosine-triphosphate (ATP) to improve the efficacy of cisplatin in the treatment of TNBC. Crylic acid-caged 2,4-dinitrophenol ( DNPA ) was developed as a novel pro-uncoupler of OxPhos. By depletion of cysteine, 2,4-dinitrophenol is released to promote oxidation and inhibit phosphorylation, which results in the generation of heat rather than ATP. Importantly, the generated heat can increase cross-linking between cisplatin and DNA, while the reduction of ATP can downregulate DNA repair enzymes. Furthermore, the depletion of both cysteine and ATP inhibits glutathione (GSH) synthesis in TNBC cells, which alleviates the GSH-mediated inactivation of cisplatin and disrupts the redox microenvironment, thereby promoting ferroptosis and apoptosis.