Beyond angiogenesis: integrating ferroptosis and metabolic rewiring for next-generation RCC therapy

The diverse group of cancers known as renal cell carcinoma can be identified by their differing genetic mutations and distinct patterns of metabolism. Recent evidence suggests that changes in cellular metabolism have a major impact on renal cancer cell viability, therapeutic resistance and disease progression. Chromophobe renal cell carcinoma (chRCC) appears to be one of the subtypes of renal cell carcinoma that exhibits a most unique pattern of metabolism; chRCC cells display both mitochondrial abnormalities and an altered redox state, in addition to an abnormality in the regulation of iron. These abnormalities suggest that there are metabolic vulnerabilities associated with the development of renal tumors that are different from those seen in clear cell RCC and papillary RCC. A recently described process, called ferroptosis, is a highly regulated process of cell death mediated by iron-dependent lipid peroxidation. Ferroptosis appears to be particularly relevant in the context of renal cancer because it is metabolically regulated and requires intact glutathione metabolism, mitochondrial function, lipid composition, and iron homeostasis. All of these processes are disrupted in renal tumors. In this review, we will synthesize our present understanding of the changes in metabolism that occur in renal cell carcinoma, with a focus on chromophobe renal cell carcinoma, and critically examine the mechanisms underlying and the therapeutic potential of inducing ferroptosis. Through integration of findings from experimental models, translational studies and emerging clinical observations, we will investigate how disruption of mitochondrial function, glutathione dependence, and regulation of iron homeostasis contribute to sensitization of renal cancer cells to ferroptotic death. Finally, we will provide a discussion of pharmacological approaches to target these pathways, mechanisms of resistance to such approaches, and issues related to the heterogeneity of renal tumors and clinical translation. Ultimately, this review will provide a broad overview of ferroptosis as a metabolically driven therapeutic strategy for renal cell carcinoma and highlight areas for future investigation and clinical development.