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
  • 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: [email protected].
  • 5. School of Life Sciences, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 6. School of Life Sciences, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
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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