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<p>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 (<i>TP53</i>)-mutant cells. Conversely, in <i>TP53</i>-wild-type (WT) cells, TAF1 phosphorylates TP53, facilitating murine double minute 2 (MDM2)-mediated TP53 degradation, which upregulates solute carrier family 7 member 11 (<i>SLC7A11</i>) 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 <i>TP53</i> status.</p>

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

  • 期刊论文

  • 发表日期：

    2026年4月30日

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  • Kehong Ye,
  • Meifu Gan,
  • Liang Sun,
  • Chaoyi Chen,
  • Xuan Lai,
  • Yinjun He,
  • Ming Zhu,
  • Weiqin Jiang,
  • Honghe Zhang

摘要

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.