TAF1 aggravates ferroptosis by promoting the ubiquitin-mediated degradation of nuclear GPX4.

Glutathione peroxidase 4 (GPX4) is a primary inhibitor of ferroptosis, a regulated form of cell death driven by the accumulation of lipid hydroperoxides. GPX4 exists in three isoforms localized in the cytosol, mitochondria, and nucleus; however, the regulatory mechanisms governing nuclear GPX4 (nGPX4) remain largely unclear. Herein, we identified TATA box-binding protein-associated factor 1 (TAF1) as a pivotal regulator of nGPX4. TAF1 phosphorylates nGPX4, leading to its lysine 11 (K11)-linked ubiquitination and proteasomal degradation, thereby promoting ferroptosis in tumor protein p53 (TP53)-mutant cells. Conversely, in TP53-wild-type (WT) cells, TAF1 phosphorylates TP53, facilitating murine double minute 2 (MDM2)-mediated TP53 degradation, which upregulates solute carrier family 7 member 11 (SLC7A11) expression and reduces cellular susceptibility to ferroptosis. Collectively, TAF1 plays dual and context-dependent roles in ferroptosis regulation, acting as both a promoter and an inhibitor depending on the TP53 status.