Abstract
Post-translational modifications (PTMs) play a critical role in cancer radioresistance, yet how they regulate ferroptosis to influence radiotherapy response remains poorly understood. Here, we show that HDAC4 promotes radiation resistance in lung cancer by inhibiting ferroptosis. Through a CRISPR screen in patient-derived organoids, we identify HDAC4 as a key mediator. Mechanistically, HDAC4 acts as an E3 SUMO ligase that SUMOylates MBD1, preventing its ubiquitination and degradation. Stabilized MBD1 represses TP53 and CYP1A1 transcription, thereby suppressing lipid reactive oxygen species formation and ferroptosis. To target HDAC4, we develop a proteolysis-targeting chimera (PROTAC), TP1, based on tasquinimod, which binds and degrades HDAC4 specifically, as confirmed by surface plasmon resonance and proteomics. TP1 exhibits stronger radiosensitizing effects than tasquinimod in lung cancer organoids and xenograft models. Our findings uncover HDAC4 as a suppressor of ferroptosis in radioresistance and present a PROTAC-based strategy to enhance radiotherapy efficacy.
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Acknowledgements
We thank Dr. Caolin Wang (Jiangxi Key Laboratory of Oncology) for technical support in PROTAC synthesis.
Funding
This study was supported by grants from the National Natural Science Foundation of China (82260496 to C.C., 82160560 to Y.S., 82360474 to L.S, 82373150 and 82573408 to K.H.), the Jiangxi Provincial Health Commission Foundation (2026L1002 to Y.S.), the Jiangxi Provincial Natural Science Foundation (20232BAB216071 to C.C.), and the Science and Technology Project of Nanchang Science and Technology Bureau and Health Commission (2025YLWS0010 to C.C.).
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Cheng, C., Sun, L., Yang, J. et al. An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73682-0
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DOI: https://doi.org/10.1038/s41467-026-73682-0
