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

BACKGROUND: Radiation dermatitis (RD) remains a major clinical complication of radiotherapy, but its upstream molecular mechanisms are incompletely understood. Increasing evidence suggests that ferroptosis-an iron-dependent form of regulated cell death-may contribute to radiation-induced tissue injury, yet its role in skin pathology and immune activation remains undefined. METHODS: We integrated multi-omics analysis, cellular co-culture, computational modeling, and in vivo validation to investigate the role of NCOA4-mediated ferritinophagy and its interplay with the cGAS-STING pathway in RD. Bulk and single-cell RNA-seq analyses were used to characterize ferroptosis-related transcriptional signatures. Biochemical assays, transmission electron microscopy, and cytokine profiling evaluated ferroptosis and inflammation in irradiated keratinocytes and macrophages. The redox-active compound Cu-ATSM was tested as a potential therapeutic modulator both in vitro and in a mouse RD model. RESULTS: Ionizing radiation (IR) induced NCOA4 upregulation and ferritin degradation in epidermal keratinocytes, leading to labile iron accumulation, lipid peroxidation, and activation of ferroptotic markers such as ACSL4. Co-culture experiments demonstrated that ferroptotic keratinocytes released DNA-associated DAMPs that activated the cGAS-STING-IFN-β axis in macrophages, forming a redox-immune feedback loop. Cu-ATSM treatment markedly suppressed ferroptosis and downstream STING activation. Docking and molecular dynamics simulations positioned Cu-ATSM within the FTH1-binding interface of NCOA4, suggesting competitive inhibition, while immunoprecipitation-MRM mass spectrometry confirmed physical association. In vivo, topical Cu-ATSM significantly ameliorated RD severity, preserved mitochondrial morphology, and reduced ferroptosis and inflammatory cytokine expression in irradiated skin. CONCLUSION: These findings identify the NCOA4-ferroptosis-cGAS-STING axis as a key pathogenic pathway linking redox imbalance to inflammation in radiation dermatitis. Cu-ATSM acts as a multimodal modulator that interferes with NCOA4-mediated ferritinophagy and mitigates ferroptosis-driven immune activation. This study establishes a mechanistic framework for ferroptosis-targeted interventions and supports Cu-ATSM as a promising therapeutic strategy for mitigating radiation-induced skin injury.