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

Kehong YE; Meifu GAN; Liang SUN; Chaoyi CHEN; Xuan LAI; Yinjun HE; Ming ZHU; Weiqin JIANG; Honghe ZHANG

doi:10.1631/jzus.B2500567

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

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Research Article | Updated：2026-04-23

TAF1 aggravates ferroptosis by promoting the ubiquitin-mediated degradation of nuclear GPX4
TAF1 aggravates ferroptosis by promoting the ubiquitin-mediated degradation of nuclear GPX4
TAF1通过促进核GPX4的泛素化降解加剧铁死亡
Journal of Zhejiang University-SCIENCE B Vol. 27, Issue 4, Pages: 359-374(2026)
Affiliations：

1.Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310058, China
2.Department of Pathology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China
3.Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou 317000, China
4.Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
5.Department of Pathology, State Key Laboratory of Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
6.Department of Colorectal Surgery and Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
Funds：
DOI：10.1631/jzus.B2500567
CLC：
CSTR：
Received：08 September 2025，

Revised：2025-11-11，

Published：23 April 2026
Accepted：

叶科宏,甘梅富,孙梁等.TAF1通过促进核GPX4的泛素化降解加剧铁死亡[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2026,27(04):359-374.

Kehong YE, Meifu GAN, Liang SUN, et al. TAF1 aggravates ferroptosis by promoting the ubiquitin-mediated degradation of nuclear GPX4[J]. Journal of Zhejiang University-SCIENCE B, 2026, 27(4): 359-374.
叶科宏,甘梅富,孙梁等.TAF1通过促进核GPX4的泛素化降解加剧铁死亡[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2026,27(04):359-374. DOI： 10.1631/jzus.B2500567.

Kehong YE, Meifu GAN, Liang SUN, et al. TAF1 aggravates ferroptosis by promoting the ubiquitin-mediated degradation of nuclear GPX4[J]. Journal of Zhejiang University-SCIENCE B, 2026, 27(4): 359-374. DOI： 10.1631/jzus.B2500567.

摘要

铁死亡是一种由脂质氢过氧化物过量累积所驱动的程序性细胞死亡。谷胱甘肽过氧化物酶4（GPX4）是其核心抑制因子。GPX4拥有胞质、线粒体与细胞核三种亚型，但对细胞核亚型（nGPX4）的调控机制，目前尚不明确。本研究鉴定出TATA框结合蛋白相关因子1（TAF1）是nGPX4的关键调控蛋白，且其作用机制因细胞

TP53

状态的不同而呈双重性：在

TP53

突变细胞中，TAF1介导的nGPX4磷酸化会触发其发生K11链接的泛素化及降解，从而促进铁死亡；而在

TP53

野生型细胞中，TAF1则通过磷酸化TP53并促进其经MDM2途径介导的降解，进而上调

SLC7A11

表达，最终抑制铁死亡。综上所述，TAF1在铁死亡进程中扮演着一种依赖于

TP53

状态的双重调控角色。

Abstract

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

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.

关键词

Keywords

references

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