2. Academic Validation
  3. The xCT/CD98 complex suppresses ferroptosis in pan-cancer via a non-canonical RACK1-mediated iron homeostasis pathway

The xCT/CD98 complex suppresses ferroptosis in pan-cancer via a non-canonical RACK1-mediated iron homeostasis pathway

  • Cell Rep. 2025 Nov 25;44(11):116563. doi: 10.1016/j.celrep.2025.116563.
Siwei Ju 1,  Lidan Jin 1,  Zhongqiu Zheng 2,  Qingna Meng 3,  Yangjun Cai 2,  Dazhi Chen 4,  Xiaoxi Ouyang 5,  Nadire Aishan 1,  Lingxiao Lu 6,  Zhanzhi Li 7,  Yongxia Chen 1,  Junchi Zhang 1,  Jiaheng Lang 1,  Qina He 1,  Bojian Xie 8,  Jichun Zhou 9,  Feiyang Ji 10,  Linbo Wang 11
Affiliations

Affiliations

  • 1 Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China; Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Sir Run Run Shaw Hospital, School of Medicine, Cancer Center of Zhejiang University, Zhejiang University, Hangzhou, China.
  • 2 Department of Thyroid and Breast Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.
  • 3 School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 4 School of Clinical Medicine, The First People's Hospital of Lin'an District, Hangzhou, Lin'an People's Hospital Affiliated to Hangzhou Medical College, Hangzhou Medical College, Hangzhou, China.
  • 5 State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 6 Department of Public Research Platform, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.
  • 7 School of Clinical Medicine, Hangzhou Medical College, Hangzhou, China.
  • 8 Department of Thyroid and Breast Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China. Electronic address: [email protected].
  • 9 Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China; Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Sir Run Run Shaw Hospital, School of Medicine, Cancer Center of Zhejiang University, Zhejiang University, Hangzhou, China. Electronic address: [email protected].
  • 10 State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: [email protected].
  • 11 Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China; Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Sir Run Run Shaw Hospital, School of Medicine, Cancer Center of Zhejiang University, Zhejiang University, Hangzhou, China; School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China. Electronic address: [email protected].
PMID: 41252251 DOI: 10.1016/j.celrep.2025.116563
Abstract

Evasion of cell death drives tumor recurrence and metastasis, yet pan-cancer mechanisms of Ferroptosis remain limited. We treated multiple tumor cell lines with Ferroptosis inducers or Anticancer agents and utilized post-translational modification proteomics including ubiquitination, acetylation, and phosphorylation during Ferroptosis. We identify a significant increase in K280 ubiquitination of the ribosomal protein RACK1. Further pan-cancer cellular experiments suggest that RACK1 may suppress Ferroptosis by regulating iron export via FPN1. Immunoprecipitation coupled with liquid chromatography-mass spectrometry reveals RACK1 interactions with CD98 and TRIM21. Ferroptosis inducers promote RACK1 K280 ubiquitination via TRIM21, and mechanistic studies confirm that TRIM21-mediated RACK1 ubiquitination affects cellular iron homeostasis. These findings indicate that, beyond the canonical GPX4 pathway, the xCT/CD98 complex can inhibit Ferroptosis via the TRIM21/RACK1/FPN1 axis. Targeting RACK1 offers a potential therapeutic strategy to sensitize tumors to Ferroptosis and overcome therapy resistance across multiple Cancer types and in people with Cancer.

Keywords

CP: Cancer; FPN1; RACK1; TRIM21; cell death; ferroptosis; proteomics.

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