2. Academic Validation
  3. YY1-induced USP43 drives ferroptosis suppression by FASN stabilization and subsequent activation of SLC7A11 in ovarian cancer

YY1-induced USP43 drives ferroptosis suppression by FASN stabilization and subsequent activation of SLC7A11 in ovarian cancer

  • Cell Death Dis. 2025 Sep 1;16(1):589. doi: 10.1038/s41419-025-07886-5.
Tianyi Zhao # 1 2 3,  Xiaojun Chen # 1 3,  Jiangchun Wu # 1 3,  Siyu Chen # 1 3,  Yu Gan 3 4,  Chaohua Liu 1 3,  Xinyu Ha 1 3,  Yangjun Wu 5 6,  Xiang Zhou 7 8 9 10,  Yong Wu 11 12,  Xiaohua Wu 13 14
Affiliations

Affiliations

  • 1 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 2 Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 3 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 4 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 5 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. wuyangjun1014@163.com.
  • 6 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. wuyangjun1014@163.com.
  • 7 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. xiangzhou@fudan.edu.cn.
  • 8 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China. xiangzhou@fudan.edu.cn.
  • 9 Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China. xiangzhou@fudan.edu.cn.
  • 10 Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, China. xiangzhou@fudan.edu.cn.
  • 11 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. docwuyong@outlook.com.
  • 12 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. docwuyong@outlook.com.
  • 13 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. wu.xh@fudan.edu.cn.
  • 14 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. wu.xh@fudan.edu.cn.
  • # Contributed equally.
PMID: 40890129 DOI: 10.1038/s41419-025-07886-5
Abstract

The Ubiquitin-Specific Protease (USP) family is a major member of the deubiquitinating enzyme family that plays important and diverse roles in multiple tumors. The roles and mechanisms of action of USP family members in ovarian Cancer are not well understood. This study aimed to screen all the USP family members and explored the specific function of USP43 in ovarian Cancer. The expression levels of USP family members in ovarian Cancer were screened using bioinformatics analysis, and the specific function of USP43 was explored through in vitro and in vivo experiments. Functional assays, including cell viability, Ferroptosis, and tumor xenograft models, were employed. In short, USP43 drives the Ferroptosis suppression by activating the expression of SLC7A11 through FASN-HIF1α pathway. USP43 is an important prognostic factor for ovarian Cancer, with its overexpression promoting ovarian Cancer progression and its knockdown inhibiting it. Mechanistically, USP43, which is transcriptionally activated by YY1, stabilizes FASN through deubiquitination, and FASN activates SLC7A11 expression by stabilizing HIF1α. Furthermore, the combination of cisplatin and the SLC7A11 inhibitor HG106 significantly inhibits the growth of ovarian tumors. Thus, targeting the USP43-FASN-HIF1α-SLC7A11 axis can inhibit Ferroptosis and promote platinum sensitivity in ovarian Cancer.

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