NCOA4-mediated ferroptosis drives cGAS-STING-dependent inflammation in radiation dermatitis: Protective modulation by...

Area of Science:

• Redox biology
• Immunology
• Dermatology

Background:

• Radiation dermatitis (RD) is a common radiotherapy complication with unclear molecular drivers.
• Ferroptosis, a form of regulated cell death, is implicated in tissue injury but its role in RD and skin inflammation is undefined.

Purpose of the Study:

• To investigate the role of NCOA4-mediated ferritinophagy and its interplay with the cGAS-STING pathway in radiation dermatitis.
• To evaluate the therapeutic potential of Cu-ATSM in mitigating radiation-induced skin injury.

Main Methods:

• Integrated multi-omics, cellular co-culture, computational modeling, and in vivo validation.
• Analyzed ferroptosis and inflammation markers in irradiated keratinocytes and macrophages.
• Tested Cu-ATSM in vitro and in a mouse RD model.

Main Results:

• Ionizing radiation induced NCOA4-mediated ferroptosis in keratinocytes, releasing DAMPs that activated the cGAS-STING-IFN-β axis in macrophages.
• Cu-ATSM suppressed ferroptosis and STING activation, acting as a competitive inhibitor of NCOA4.
• Topical Cu-ATSM treatment ameliorated RD severity, reduced ferroptosis, and decreased inflammatory cytokines in vivo.

Conclusions:

• The NCOA4-ferroptosis-cGAS-STING axis is a key pathway linking redox imbalance to inflammation in RD.
• Cu-ATSM demonstrates multimodal therapeutic effects by inhibiting ferroptosis and ferroptosis-driven immune activation.
• Cu-ATSM is a promising therapeutic strategy for radiation-induced skin injury.