Reprogramming Proton-Coupled Electron Transfer in Living Cancer Cells to Eradicate Tumors

Intracellular proton-coupled electron transfer (PCET) governs cellular metabolism and fate, and its dysregulation is closely associated with disease progression. In normal cells, PCET into the electron transport chain supports ATP production and cellular growth. In cancer cells, however, overexpressed lactate dehydrogenase (LDH) redirects PCET to pyruvate, producing lactate and thereby sustaining tumor growth, proliferation, and metastasis. Reprogramming LDH-driven PCET in living tumors therefore represents an attractive antitumor strategy, yet no artificial catalyst has been shown to outcompete LDH and reprogram PCET in living cells. Here, we report an organoiridium catalyst, Ir^III(Cp*)-CN, that captures proton-coupled electrons from NADH and transfers them to protons to generate H₂ under ultrasound irradiation at physiological pH. In living cancer cells, Ir^III(Cp*)-CN outcompetes LDH and redirects LDH-driven pyruvate reduction and lactate production toward proton reduction and H₂ generation. This PCET-reprogramming process converts a tumor-promoting, lactate-producing reaction into a tumor-suppressive, H₂-generating reaction, suppressing lactate and ATP production and markedly inhibiting tumor growth with minimal toxicity to normal cells and tissues. These findings establish a framework for reprogramming intracellular PCET via artificial catalysts that outcompete endogenous enzymes, offering a strategy for treating diseases associated with dysregulated cellular redox metabolism.