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While multiple factors contribute to IVDD pathogenesis, cellular senescence has emerged as a critical risk factor associated with both the incidence and progression of IVDD. Aging and other damage factors drive nucleus pulposus cells (NPCs) toward a senescent phenotype characterized by increased secretion of proinflammatory factors, resulting in NPC dysfunction and tissue degeneration, which are hallmarks of IVDD. In this study, we demonstrated that PRMT2 deficiency disrupted arginine methylation-ubiquitination crosstalk, driving NPC inflammatory senescence and accelerating IVDD progression. Mechanistically, PRMT2 loss reduced FBXO7 methylation at Arg504, promoting the FBXO7\u2013MED12 interaction to facilitate MED12 ubiquitination and subsequent proteasomal degradation. MED12 deficiency induced pathological R-loop accumulation, which activated the cytosolic DNA\u2013sensing cGAS\/STING axis, triggering inflammatory response cascades. Notably, engineered extracellular vesicles delivering MED12-overexpressing plasmids significantly inhibited NPC senescence and attenuated IVDD progression. Together, our findings establish that dysregulated methylation-ubiquitination crosstalk critically drives IVDD progression and reveal MED12 as a promising therapeutic target for ameliorating the impact of IVDD.<\/jats:p>\n                  <jats:p\/>\n                  <jats:p>PRMT2 deficiency\u2012mediated methylation-ubiquitination crosstalk of MED12 promotes R-loop\/cGAS\/STING axis-dependent IVDD progression.<\/jats:p>","DOI":"10.1172\/jci197274","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T18:27:54Z","timestamp":1782844074000},"source":"Crossref","is-referenced-by-count":1,"title":["Dysregulated methylation-ubiquitination crosstalk accelerates intervertebral disc degeneration via MED12 destabilization and cGAS\/STING activation"],"prefix":"10.1172","volume":"136","author":[{"given":"Huaizhen","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University 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