2. Academic Validation
  3. O-GlcNAcylation regulates the stability of transferrin receptor (TFRC) to control the ferroptosis in hepatocellular carcinoma cells

O-GlcNAcylation regulates the stability of transferrin receptor (TFRC) to control the ferroptosis in hepatocellular carcinoma cells

  • Redox Biol. 2024 May 8:73:103182. doi: 10.1016/j.redox.2024.103182.
Xunyu Zhou 1,  Yida Wang 1,  Xiaoyu Li 2,  Jing Zhou 3,  Wanyi Yang 1,  Xin Wang 1,  Sitong Jiao 1,  Weibo Zuo 1,  Ziming You 1,  Wantao Ying 4,  Chuanfang Wu 5,  Jinku Bao 6
Affiliations

Affiliations

  • 1 School of Life Sciences, Sichuan University, Chengdu, 610041, China.
  • 2 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
  • 3 West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 4 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China. Electronic address: yingwantao@ncpsb.org.cn.
  • 5 School of Life Sciences, Sichuan University, Chengdu, 610041, China. Electronic address: wuchuanfang@scu.edu.cn.
  • 6 School of Life Sciences, Sichuan University, Chengdu, 610041, China. Electronic address: baojinku@scu.edu.cn.
PMID: 38744192 DOI: 10.1016/j.redox.2024.103182
Abstract

Ferroptosis is an iron-dependent programmed cell death (PCD) enforced by lipid peroxidation accumulation. Transferrin Receptor (TFRC), one of the signature proteins of Ferroptosis, is abundantly expressed in hepatocellular carcinoma (HCC). However, post-translational modification (PTM) of TFRC and the underlying mechanisms for Ferroptosis regulation remain less understood. In this study, we found that TFRC undergoes O-GlcNAcylation, influencing Erastin-induced Ferroptosis sensitivity in hepatocytes. Further mechanistic studies found that Erastin can trigger de-O-GlcNAcylation of TFRC at serine 687 (Ser687), which diminishes the binding of ubiquitin E3 Ligase membrane-associated RING-CH8 (MARCH8) and decreases polyubiquitination on lysine 665 (Lys665), thereby enhancing TFRC stability that favors labile iron accumulation. Therefore, our findings report O-GlcNAcylation on an important regulatory protein of Ferroptosis and reveal an intriguing mechanism by which HCC Ferroptosis is controlled by an iron metabolism pathway.

Keywords

Ferroptosis; Hepatocellular carcinoma; O‐GlcNAcylation; TFRC; Ubiquitination.

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