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Although mutations and dysregulation of KMT2 family members have been implicated in various cancers, their functional significance in meningioma remains unclear. While NF2 alterations are the most common drivers of meningioma pathogenesis, the mechanisms regulating NF2 transcription in NF2\u2010intact tumors are poorly understood. Here, we demonstrate that KMT2C expression is markedly reduced in high\u2010grade meningiomas and that loss of KMT2C promotes proliferation and invasion in NF2\u2013wild\u2010type meningioma cells. Mechanistically, KMT2C deficiency suppresses NF2 transcription and inactivates Hippo signaling, leading to enhanced oncogenic activity and increased sensitivity to ferroptosis. Loss of KMT2C impairs the acetyltransferase activity of CBP\/EP300, resulting in a global reduction of H3K27ac and transcriptional silencing of NF2. Pharmacological restoration of histone acetylation with the HDAC inhibitor Trichostatin A (TSA) effectively suppressed tumor growth. Collectively, our findings identify KMT2C as a key epigenetic regulator linking promoter histone acetylation, NF2\u2013Hippo pathway activity, and ferroptosis susceptibility. These results provide mechanistic insights into high\u2010grade meningioma progression and highlight ferroptosis induction and epigenetic modulation as promising therapeutic strategies for NF2\u2013wild\u2010type, KMT2C\u2010deficient meningiomas.<\/jats:p>","DOI":"10.1002\/advs.202522756","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T18:53:39Z","timestamp":1770317619000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["KMT2C Loss Promotes NF2\u2010Wildtype Meningioma Progression and Ferroptosis Sensitivity via Epigenetic Repression of Hippo Signaling"],"prefix":"10.1002","volume":"13","author":[{"given":"Liuchao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital with Nanjing Medical University  Nanjing Jiangsu P. R. 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