ZHEJIANG — Researchers from Zhejiang University School of Medicine, Zhejiang Cancer Hospital, Taizhou Hospital of Zhejiang Province, and Peking Union Medical College Hospital published a study in the Journal of Zhejiang University-SCIENCE B in 2026 showing that TATA box-binding protein-associated factor 1 (TAF1) regulates ferroptosis through opposing mechanisms in cancer cells depending on their TP53 status. The study, authored by Ye, K., et al. and published in Volume 27, Issue 4 with DOI: 10.1631/jzus.B2500567, reveals that TAF1 acts as a molecular switch whose role in ferroptosis is determined by whether tumor protein p53 (TP53) is mutated or wild-type.
Ferroptosis is a form of programmed cell death that has gained attention in cancer research for its potential to eliminate tumor cells resistant to other forms of cell death like apoptosis. Glutathione peroxidase 4 (GPX4) protects cells from ferroptosis by neutralizing lipid peroxides, and while GPX4 exists in cytosolic, mitochondrial, and nuclear forms, the regulation of nuclear GPX4 (nGPX4) remains poorly understood. The researchers screened pan-cancer datasets and identified TAF1 as a candidate linked to reduced expression of multiple ferroptosis suppressors.
In experiments using TAF1-knockout colorectal and ovarian cancer cell models treated with the GPX4 inhibitor (1S,3R)-RSL3, the team observed that TAF1 deletion reduced ferroptosis sensitivity in TP53-mutant or TP53-null cells but increased sensitivity in TP53-wild-type cells. In TP53-mutant cells, TAF1 interacted with nGPX4 and promoted its degradation via lysine 11 (K11)-linked ubiquitination. In TP53-wild-type cells, TAF1 enhanced MDM2-mediated degradation of TP53, which led to increased expression of SLC7A11 and reduced ferroptosis susceptibility.
Mouse xenograft experiments using SW620 cells, which carry TP53 mutations, supported TAF1’s role in promoting ferroptosis in this context. The findings suggest that TP53 status may help predict tumor response to ferroptosis-inducing therapies. In TP53-mutant tumors with high TAF1 expression, such inducers could be more effective, whereas in TP53-wild-type tumors, low TAF1 levels may correlate with greater sensitivity to these approaches.
"The study shows why ferroptosis should not be understood through a single molecular route," the authors wrote. "TAF1 behaves more like a context-sensitive switch than a simple promoter or suppressor of ferroptosis." The work highlights nGPX4 degradation and ubiquitin-mediated protein control as promising areas for future research, though further studies are needed to identify the specific enzymes involved and determine whether targeting TAF1-related pathways can enhance personalized cancer treatment.