DANGER/ITPRIP-mediated iron homeostasis mediates ferroptosis resistance and presents a potential therapeutic target...

Clear cell renal cell carcinoma (ccRCC) exhibits unique metabolic reprogramming characterized by disrupted iron homeostasis, primarily due to inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. This iron dysregulation creates a therapeutic opportunity through ferroptosis, an iron-dependent form of regulated cell death. However, the specific mechanisms enabling ccRCC cells to evade ferroptosis in high-iron microenvironments remain poorly understood, limiting targeted therapy development. In this study, we identified DANGER (inositol 1,4,5-trisphosphate receptor interacting protein, ITPRIP) as an oncoprotein specifically overexpressed in ccRCC. DANGER establishes a cytoprotective axis by promoting nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation, leading to ferritin heavy chain 1 (FTH1) upregulation. The DANGER/NRF2/FTH1 signaling cascade enhances iron storage, reduces cytotoxic labile iron pools, and suppresses lethal lipid peroxidation, conferring robust ferroptosis resistance. Under high-iron stress, ccRCC cells collectively upregulate the pro-ferroptotic enzyme 5-lipoxygenase (ALOX5) alongside this protective axis, creating a ferroptosis pre-conditioning state that elevates the ferroptosis initiation threshold. Translationally, we discovered that deferasirox (DFX), a clinically approved iron chelator, functions as a direct DANGER inhibitor that disrupts this protective axis, resensitizes cells to ferroptosis, and suppresses tumor proliferation and migration. This work establishes DANGER-mediated iron homeostasis as a core mechanism of ferroptosis resistance in ccRCC and validates DFX as a mechanistically grounded therapeutic strategy.