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

Area of Science:

• Oncology
• Cellular Biology
• Biochemistry

Background:

• Tumor recurrence and metastasis are driven by cancer cells evading cell death.
• Mechanisms of ferroptosis, a regulated cell death pathway, are not fully understood across all cancer types.
• Understanding ferroptosis regulation is crucial for developing effective cancer therapies.

Purpose of the Study:

• To investigate novel pan-cancer mechanisms regulating ferroptosis.
• To identify key proteins and pathways involved in ferroptosis evasion.
• To explore potential therapeutic targets for sensitizing tumors to ferroptosis.

Main Methods:

• Utilized post-translational modification proteomics (ubiquitination, acetylation, phosphorylation) in multiple tumor cell lines treated with ferroptosis inducers or anticancer agents.
• Performed pan-cancer cellular experiments to assess RACK1 function in ferroptosis.
• Employed immunoprecipitation coupled with liquid chromatography-mass spectrometry to identify protein interactions.

Main Results:

• Identified increased K280 ubiquitination of ribosomal protein RACK1 during ferroptosis.
• Demonstrated that RACK1 may suppress ferroptosis by regulating iron export via FPN1.
• Revealed RACK1 interacts with CD98 and TRIM21, with TRIM21 mediating RACK1 ubiquitination and affecting iron homeostasis.

Conclusions:

• The xCT/CD98 complex inhibits ferroptosis via the TRIM21/RACK1/FPN1 axis, independent of the canonical GPX4 pathway.
• Targeting RACK1 presents a potential therapeutic strategy to enhance ferroptosis sensitivity in tumors.
• This approach could help overcome therapy resistance in various cancer types.