The role of ferroptosis in renal cell carcinoma: molecular mechanisms and therapeutic implications.

Of the numerous regulatory cell death mechanisms, ferroptosis has emerged as a pivotal player in the pathobiology of renal cell carcinoma (RCC), particularly the clear-cell subtype (ccRCC). This iron-dependent form of cell death, characterized by the catastrophic accumulation of lipid peroxides, is intimately linked to the unique metabolic landscape of ccRCC, including its lipid-rich environment and reliance on specific antioxidant pathways. This review comprehensively synthesizes the current understanding of the molecular mechanisms governing ferroptosis in RCC. We delineate the core regulatory machinery, including the system xc-/GSH/GPX4 axis and key lipid-metabolizing enzymes like ACSL3 and ACSL4, and explore the multifaceted transcriptional, epigenetic, and metabolic networks that fine-tune ferroptotic sensitivity. Beyond summarizing established paradigms, this review places particular emphasis on the multilayer regulatory networks (including transcriptional, epigenetic, and metabolic rewiring) that fine-tune ferroptotic sensitivity, and critically examines the emerging role of ferroptosis suppression as a core mechanism of resistance to tyrosine kinase inhibitors. We also dissect the intricate crosstalk between ferroptosis and the tumor immune microenvironment, highlighting its impact on prognosis and immunotherapy response. Finally, we survey the evolving therapeutic landscape, encompassing small-molecule inducers, natural compounds, and innovative combination strategies designed to trigger ferroptosis. This comprehensive overview underscores ferroptosis as a critical vulnerability and a promising therapeutic target to overcome treatment resistance in RCC.