Cell death resistance is a hallmark of cancer. Many cancer therapies are designed to induce apoptosis, the best-known cell death mechanism, in cancer cells. However, in many cases, cancer therapies are ineffective in inducing apoptosis during cancer treatment partly due to genetic alterations of apoptotic pathways in human cancers, leading to therapy resistance and tumor recurrence. Thus, studying mechanisms of alternative regulated cell death may provide novel strategies in cancer treatment.

Ferroptosis is an iron-dependent form of nonapoptotic cell death that is induced by a type of lipid damage on cellular membranes called lipid peroxidation. Certain drugs known as ferroptosis inducers c...

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Cell death resistance is a hallmark of cancer. Many cancer therapies are designed to induce apoptosis, the best-known cell death mechanism, in cancer cells. However, in many cases, cancer therapies are ineffective in inducing apoptosis during cancer treatment partly due to genetic alterations of apoptotic pathways in human cancers, leading to therapy resistance and tumor recurrence. Thus, studying mechanisms of alternative regulated cell death may provide novel strategies in cancer treatment.

Ferroptosis is an iron-dependent form of nonapoptotic cell death that is induced by a type of lipid damage on cellular membranes called lipid peroxidation. Certain drugs known as ferroptosis inducers can have potent cell killing effects by inducing ferroptosis in cancer cells, and hold great potentials in cancer therapy. Recent studies from us and others have identified ferroptosis as a key tumor suppression mechanism and shown that ferroptosis inactivation, like apoptosis inactivation, contributes to tumor development. However, in contrast to our deep knowledge of apoptosis in cancer, our understanding of ferroptosis in tumor biology and cancer therapy is relatively rudimentary, limiting our capability to target ferroptosis in cancer treatment.

In this application, we propose to understand how ferroptosis is controlled at molecular levels in cancer cells and to design and test rationale therapies of combining ferroptosis inducers with other compounds in cancer treatment using rigorous preclinical models. Our proposed studies will not only have significant impact on our understanding of the fundamental mechanisms of ferroptosis but also provide novel therapeutic strategies to target ferroptosis in cancer treatment.

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