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Nonetheless, the efficacy of radiotherapy is constrained by the inherent radioresistance of meningiomas, attributed to their proficient DNA damage repair and robust cell cycle checkpoint regulation. These biological barriers, along with anatomical constraints of avoiding damage to adjacent neural tissues, restrict dose escalation and therapeutic gains. Histone deacetylases (HDACs) are mediators of radioresistance in meningioma, and their inhibition can be a rational approach to enhance the therapeutic efficacy. This study systematically investigated the radiosensitising potential of dacinostat, a pan-HDACi, and demonstrated its superior synergy with radiation compared to other FDA-approved HDACis. Pre-treatment with dacinostat effectively suppressed radiation-induced HDAC activity, resulting in sustained DNA damage, prolonged G2\/M arrest, and enhanced apoptosis. Mechanistic analyses revealed that radiosensitisation was associated with RAD51 downregulation, inhibition of DNA-PKcs activity, modulation of p53 phosphorylation, and attenuation of SUMOylation-dependent DNA repair signalling. Transcriptomic profiling underscored cell-cycle regulation and DNA-repair pathways in response to combination treatment. Meanwhile, proteomic data implicated the modulation of SUMOylation as a central mediator of the observed radiosensitisation. Importantly, in physiologically relevant 3D spheroid models derived from patient meningioma specimens, the combined treatment synergistically augmented cell death, supporting the translational potential of this therapeutic strategy. Overall, this work establishes dacinostat as a promising radiosensitiser that compromises DNA repair fidelity and moduflates SUMOylation-associated pathways, thereby enhancing efficacy in treatment-resistant meningiomas. These findings provide a compelling preclinical basis to advance dacinostat into clinical assessment for the management of aggressive meningioma.<\/jats:p>","DOI":"10.1038\/s41419-026-08899-4","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T14:21:47Z","timestamp":1780410107000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting HDACs with dacinostat amplifies radiation-induced DNA damage via sustained phosphorylated p53 and repair inhibition in aggressive meningioma"],"prefix":"10.1038","volume":"17","author":[{"given":"Shahana","family":"Shaji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1992-0961","authenticated-orcid":false,"given":"Juri","family":"Na","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1951-1025","authenticated-orcid":false,"given":"C. 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