Dear Editor,

p53 acts as a transcription factor to modulate various types of cellular processes to suppress tumor development (Tackmann and Zhang, 2017). The exquisite regulation of p53 functions is of vital importance for cell fate decisions. Although it is well accepted that p53-mediated cell-cycle arrest, senescence, and apoptosis serve as major tumor suppression mechanisms, recent studies suggest that other unconventional activities such as ferroptosis are also critically involved in its tumor suppressor function (Li et al., 2012). We and others found that p53 plays an important role in modulating ferroptotic responses through its metabolic targets (Jiang et al., 2015; Jennis et al., 2016; Wang et al., 2016). Ferroptosis is a regulated form of iron-dependent, non-apoptotic cell death characterized by excessive reactive oxygen species (ROS) generation and accumulation of lipid peroxidates (Stockwell et al., 2020). Lipid peroxides are normally eliminated by glutathione peroxidase 4 (GPX4) and its co-factor glutathione (GSH), which convert lipid hydroperoxides to non-toxic lipid alcohols. Thus, ferroptosis can be artificially induced by pharmacological agents that disrupt this lipid repair system, allowing lethal accumulation of lipid peroxides. Such agents include direct GPX4 enzymatic inhibitors, as well as the small molecule erastin, which suppress glutathione synthesis and indirectly suppress GPX4 activation (Stockwell et al., 2020). Although activation of p53 expression is able to modulate ferroptosis induced by GPX4 inhibition in certain cell types (Jiang et al., 2015), p53-mediated ferroptotic responses are also observed upon ROS-induced stress, apparently through a GPX4-independent manner (Chu et al., 2019). Nevertheless, the molecular factors that modulate p53-dependent ferroptosis upon ROS stress need further elucidation. Sirt3 is a NAD-dependent deacetylase predominantly localized in mitochondria, which functions in multiple metabolic pathways, including electron transport chain, fatty acid oxidation, amino acid metabolism, redox balance, and the tricarboxylic acid (TCA) cycle (Van de Ven et al., 2017). Here, we identified Sirt3 as a novel repressor in p53-mediated ferroptosis induced by ROS stress.