The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma

Despite recent advances, the poor outcomes of renal cell carcinoma (RCC) still necessitate novel therapeutics. RCC is highly susceptible to ferroptosis, a novel form of regulated cell death with disease relevance. While ferroptosis may have therapeutic potential, much remains unknown about the determinants of ferroptosis susceptibility. We found that the ferroptosis susceptibility is highly influenced by cell confluency. RCC grown at low density is highly susceptible to ferroptosis, but exhibits resistance at high density. Because cell density regulates Hippo-YAP/TAZ pathway, we investigated the roles of Hippo pathway effectors in the ferroptosis. TAZ is abundantly expressed in RCC and undergoes density-dependent nuclear/cytosolic translocation. TAZ removal confers ferroptosis resistance, while overexpression TAZS89A sensitizes cells to ferroptosis. Furthermore, TAZ regulates the expression of EMP1 that, in turn, induces the expression of NOX4, a renal-enriched ROS-generating enzyme essential for ferroptosis. Collectively, the cell density-regulated ferroptosis is mediated by TAZ through the regulation of EMP1-NOX4, suggesting its therapeutic potential for RCC and other TAZ-activated tumors.