Dysregulated methylation‒ubiquitination crosstalk accelerates intervertebral disc degeneration via MED12 destabilization and cGAS/STING activation

Huaizhen Liang; Dingchao Zhu; Zhi Du; Xinyu Li; Rui Shi; Jie Lei; Bide Tong; Hanpeng Xu; Di Wu; Xingyu Zhou; Yifan Du; Zixuan Ou; Junyu Wei; Shuchang Peng; Wencan Ke; Zhiwei Liao; Bingjin Wang; Kun Wang; Xiaobo Feng; Yu Song; Cao Yang

doi:10.1172/JCI197274

¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

²Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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J Clin Invest. https://doi.org/10.1172/JCI197274.
Copyright © 2026, Liang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 30, 2026 - Version history

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, yet clinically, there remains no effective therapeutic approach to reverse its progression, imposing a substantial socioeconomic burden. 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. Ageing and other damage factors drive nucleus pulposus cells (NPCs) towards 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 Arg 504, promoting the FBXO7-MED12 interaction to facilitate MED12 ubiquitination and subsequent proteasomal degradation. MED12 deficiency induced pathological R-loop accumulation, which activated the cytosolic DNA-sensing cGAS-STING axis, triggering inflammatory response cascades. Notably, engineered extracellular vesicles (EVs) delivering MED12-overexpressing plasmids effectively inhibited NP cell 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.

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Dysregulated methylation‒ubiquitination crosstalk accelerates intervertebral disc degeneration via MED12 destabilization and cGAS/STING activation

Huaizhen Liang,¹ Dingchao Zhu,¹ Zhi Du,¹ Xinyu Li,¹ Rui Shi,¹ Jie Lei,¹ Bide Tong,¹ Hanpeng Xu,¹ Di Wu,¹ Xingyu Zhou,¹ Yifan Du,¹ Zixuan Ou,¹ Junyu Wei,¹ Shuchang Peng,¹ Wencan Ke,¹ Zhiwei Liao,¹ Bingjin Wang,¹ Kun Wang,² Xiaobo Feng,² Yu Song,² and Cao Yang²

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Dysregulated methylation‒ubiquitination crosstalk accelerates intervertebral disc degeneration via MED12 destabilization and cGAS/STING activation

Huaizhen Liang,1 Dingchao Zhu,1 Zhi Du,1 Xinyu Li,1 Rui Shi,1 Jie Lei,1 Bide Tong,1 Hanpeng Xu,1 Di Wu,1 Xingyu Zhou,1 Yifan Du,1 Zixuan Ou,1 Junyu Wei,1 Shuchang Peng,1 Wencan Ke,1 Zhiwei Liao,1 Bingjin Wang,1 Kun Wang,2 Xiaobo Feng,2 Yu Song,2 and Cao Yang2

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Huaizhen Liang,¹ Dingchao Zhu,¹ Zhi Du,¹ Xinyu Li,¹ Rui Shi,¹ Jie Lei,¹ Bide Tong,¹ Hanpeng Xu,¹ Di Wu,¹ Xingyu Zhou,¹ Yifan Du,¹ Zixuan Ou,¹ Junyu Wei,¹ Shuchang Peng,¹ Wencan Ke,¹ Zhiwei Liao,¹ Bingjin Wang,¹ Kun Wang,² Xiaobo Feng,² Yu Song,² and Cao Yang²