Abstract
Resistance to neoadjuvant chemoradiotherapy in rectal cancer diminishes survival benefits, potentially due to dysregulated lipid metabolism, though the mechanisms are unclear. Using the MSigDB database and GSE68204 cohort, we identified lipid metabolism genes linked to radiotherapy resistance. We developed resistant cell lines and xenograft models, and through multi-algorithm analysis (SVM-RFE, RF, LASSO), pinpointed key genes. Molecular mechanisms were explored via Western blotting, co-immunoprecipitation, molecular docking, and functional assays, validated in patient-derived organoids. Our study found that radiotherapy-resistant rectal cancer shows a lipid accumulation phenotype, with an inverse relationship between lipid droplet deposition and radiosensitivity in resistant cell models. The multi-algorithm screening identified GDPD5 as a key regulator. Silencing GDPD5 reduced lipid accumulation and increased radiosensitivity. Mechanistically, GDPD5 competes with CD55, disrupting its interaction with EGFR and promoting EGFR nuclear translocation, which suppresses p53 and leads to lipid buildup and radiotherapy resistance in tumors. Clinical samples showed high GDPD5 and low CD55 levels correlate with EGFR nuclear localization. Patient-derived organoids with high GDPD5 also showed increased radiotherapy resistance. Our findings indicate that GDPD5 facilitates EGFR nuclear translocation by binding to CD55, suppressing p53, and causing lipid accumulation and radiotherapy resistance in tumors. Targeting the GDPD5-CD55-EGFR interaction may enhance radiosensitivity.
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Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. RNA-seq data for HCT116 (GSE319208) were downloaded from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/).
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The mechanistic scheme of this study was drawn by Biorender (www.biorender.com).
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This work was supported by Scientific Research Program for Young Talents of China National Nuclear Corporation, Gusu Health Talent Research Program (GSWS2023043), Suzhou Science and Technology Development Program (SYW2025102), Suzhou Radiotherapy Clinical Medical Center (Szlcyxzx202103), and Young Talent Support Project of the Second Affiliated Hospital of Soochow University (XKTJ-RC202408).
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RQZ, MYL, and YS initiated and designed the research. Experimental work wasconducted by RQZ, MYL, and YS, with data analysis performed by LZ, YTS, LMJ, and YQZ. QLP wrote the manuscript and supervised the study, with all authors approving the final version.
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In vivo experiments met relevant ethical guidelines for animal research, followed AstraZeneca’s global bioethics policy, and had the approval of the ethical committee of Soochow University (Approval Number: SUDA202411A1189). All human tissue research in this study had the approval of the ethics committees of the Second Affiliated Hospital of Soochow University (Approval Number: JD-LK2022167-IR02). Informed consent was obtained from all participants involved in this study.
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Zhu, R., Li, M., Shen, Y. et al. GDPD5-CD55-EGFR competitive binding axis regulates radioresistance and lipid accumulation in rectal cancer. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08711-3
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DOI: https://doi.org/10.1038/s41419-026-08711-3
