The overall goal of this proposal is to decipher iron redox cycles in ferroptosis-based cancer therapy. While many cancer therapies are designed to induce apoptosis, a type of cell death, it is known that cell death resistance, to apoptosis in particular, is a predominant hallmark of cancer. Therefore, many drugs are ineffective, in part due to the genetic alterations of apoptotic pathways in cancers, leading to therapy resistance and tumor recurrence. Currently, clinical trials are underway for potential drug candidates that target a different cell death pathway involving iron, known as ferroptosis. However, despite a promising decade of research in this area, few ferroptosis-based cancer d...

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The overall goal of this proposal is to decipher iron redox cycles in ferroptosis-based cancer therapy. While many cancer therapies are designed to induce apoptosis, a type of cell death, it is known that cell death resistance, to apoptosis in particular, is a predominant hallmark of cancer. Therefore, many drugs are ineffective, in part due to the genetic alterations of apoptotic pathways in cancers, leading to therapy resistance and tumor recurrence. Currently, clinical trials are underway for potential drug candidates that target a different cell death pathway involving iron, known as ferroptosis. However, despite a promising decade of research in this area, few ferroptosis-based cancer drugs have been approved, because the mechanism of ferroptosis is still poorly understood, with the role of iron being the key missing piece to the puzzle. To fill this gap in our knowledge of the ferroptosis mechanism, we propose to develop and apply novel DNAzyme-based sensors to: 1) visualize the distribution of iron redox states during ferroptosis in different organelles of cells and in mouse models; 2) correlate this information with the effects of known ferroptosis-inducing drugs and genes that regulate iron and its redox state distributions in different stages of ferroptosis; and 3) perform large-scale screens to identify new regulatory genes that may serve as novel targets for cancer therapy. By focusing on the central role of iron in ferroptosis that differentiates it from apoptosis and other cell death pathways, we will fill a major gap in the existing knowledge about ferroptosis-based cancer therapy. The insights gained will contribute to a comprehensive understanding of the ferroptosis mechanism, enhance our knowledge of current drugs, facilitate the design of more selective drugs for cancer therapy, and unlock the full potential of ferroptosis as an effective therapeutic approach for cancer.

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