Ferroptosis has become a promising area in cancer research because it may provide a way to target tumor cells that evade other better-known forms of programmed cell death, such as apoptosis and necroptosis. Glutathione peroxidase 4 (GPX4) is a central defense against ferroptosis, neutralizing the lipid peroxides that can damage cell membranes. GPX4 exists in cytosolic, mitochondrial, and nuclear forms, but the regulation of nGPX4 remains much less understood. At the same time, tumor protein p53 (TP53) mutations are common in cancer and can reshape cellular stress responses. Due to these challenges, further research is needed to clarify how nGPX4 is regulated and how this regulation affects ferroptosis across different genetic backgrounds.
Researchers from Zhejiang University School of Medicine, Zhejiang Cancer Hospital, Taizhou Hospital of Zhejiang Province, and Peking Union Medical College Hospital published (DOI: 10.1631/jzus.B2500567) the study in Journal of Zhejiang University-SCIENCE B, Volume 27, Issue 4, in 2026. The article reports that TATA box-binding protein-associated factor 1 (TAF1) controls ferroptosis through opposite mechanisms in TP53-mutant and TP53-wild-type cancer cells.
The researchers began by screening pan-cancer datasets to identify possible ferroptosis drivers and found TAF1 as a candidate associated with reduced expression of several ferroptosis suppressors. They then used TAF1-knockout colorectal and ovarian cancer cell models and treated cells with the GPX4 inhibitor (1S,3R)-RAS-selective lethal 3 (RSL3). The results revealed a context-dependent pattern: knockout of TAF1 reduced ferroptosis sensitivity in TP53-mutant or TP53-null cells but increased ferroptosis sensitivity in TP53-wild-type cells. Mechanistically, in TP53-mutant cells, TAF1 interacted with nGPX4 and promoted lysine 11 (K11)-linked ubiquitination, a protein-tagging process that marks nGPX4 for proteasomal degradation. This weakened cellular antioxidant protection and made ferroptosis more likely. In TP53-wild-type cells, TAF1 instead promoted murine double minute 2 (MDM2)-mediated TP53 degradation, increasing solute carrier family 7 member 11 (SLC7A11) expression and reducing ferroptosis susceptibility. Mouse xenograft experiments using SW620 cells further supported the role of TAF1 in enhancing ferroptosis in TP53-mutant tumors.
The authors stated the study shows why ferroptosis should not be understood through a single molecular route. They said TAF1 behaves more like a context-sensitive switch than a simple promoter or suppressor of ferroptosis. By connecting TAF1 activity with nGPX4 stability, TP53 signaling, and SLC7A11 expression, this work offers a clearer explanation for why cancer cells with different TP53 backgrounds may show sharply different responses to ferroptosis-inducing stress.
These findings may support more precise approaches to ferroptosis-based cancer therapy. The study suggests that TP53 status could help predict whether a tumor is more likely to respond to ferroptosis-inducing strategies. In TP53-mutant tumors with high TAF1 expression, ferroptosis inducers may have greater therapeutic potential, whereas in TP53-wild-type tumors, low TAF1 expression may indicate better sensitivity to such approaches. The work also identifies nGPX4 degradation and ubiquitin-mediated protein control as promising directions for future investigation. Further studies are needed to define the enzymes involved and test whether targeting TAF1-related pathways can improve personalized cancer treatment.
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References
DOI
10.1631/jzus.B2500567
Original Source URL
https://doi.org/10.1631/jzus.B2500567
Funding information
This work was supported by the National Natural Science Foundation of China (Nos. 82473008, 82173223, and 82303644), the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (No. 2019-I2M-5-044), and the Zhejiang Medical and Health Science and Technology Project (No. 2025KY439), China.
About Journal of Zhejiang University-SCIENCE B
Journal of Zhejiang University-SCIENCE B is an international peer-reviewed journal covering research in biomedicine and biotechnology. Its scope spans a wide range of fields, including medicine, genetics, biochemistry, pharmacology, agriculture, food science, botany, zoology, ecology, and environmental science. Published monthly, the journal provides a platform for high-quality research articles, reviews, correspondence, perspectives, and other scholarly contributions. It is indexed in major international databases, including Science Citation Index Expanded (SCI-E), Scopus, MEDLINE, and PubMed Central (PMC). The journal is ranked in JCR Q1 and is among the top 5% by Scopus CiteScore, reflecting its growing academic influence. Current priority research areas include oncology, immunology, gene editing, neuroscience, and ecology. As a hybrid journal, it supports both traditional subscription-based publishing and open access options.