Mitophagy Reprograms Lactate Metabolism to Suppress THBS1 via H3K18la Reduction, Alleviating Intervertebral Disc Degeneration
Mitophagy alleviates intervertebral disc degeneration (IVDD) by suppressing cGAS-STING and NLRP3 inflammasome-mediated pyroptosis pathways; however, its metabolic regulatory mechanism remains unexplored. Herein, we discovered that mitophagy activator TJ0113 drives metabolic reprogramming characterized by substantially reduced lactate production in senescent nucleus pulposus (NP) cells. This decline directly diminishes histone H3 lysine 18 lactylation (H3K18la), consequently suppressing transcription of the pro-inflammatory gene thrombospondin-1 (THBS1) and blocking downstream inflammatory cascades in IVDD progress. Through combined genetic silencing of THBS1 and pharmacological inhibition of lactate generation, we establish the lactate-H3K18la-THBS1 axis as the essential mechanism mediating mitophagy's anti-inflammatory effects. Our work provides the first evidence that mitophagy orchestrates a metabolic-epigenetic regulatory axis (lactate-H3K18la-THBS1), unveiling novel therapeutic targets for IVDD and paving the way for epigenetic therapies against disc degeneration.
Authors
- Minjun Yao (ORCID: https://orcid.org/0000-0002-0287-1745)
- Chengzhen Liang (ORCID: https://orcid.org/0000-0002-2948-2141)
- Hongguang Xia (ORCID: https://orcid.org/0000-0003-3044-9282)
- Kanbin Wang
- Xiaohua Yu (ORCID: https://orcid.org/0000-0003-4257-8081)
- Ruijie Chen
- Jianbin Xu (ORCID: https://orcid.org/0000-0003-0505-2160)
- Xiaoxiao Ji
- Fangcai Li (ORCID: https://orcid.org/0000-0002-2402-781X)
- Hao Li (ORCID: https://orcid.org/0000-0002-5274-9350)
- Yi Li (ORCID: https://orcid.org/0000-0002-2928-1358)
- Feng Cheng (ORCID: https://orcid.org/0000-0002-0148-7311)
- Han Zhou (ORCID: https://orcid.org/0009-0003-7472-3244)
- Chao Yu (ORCID: https://orcid.org/0000-0002-3744-9413)
- Ronghao Wang (ORCID: https://orcid.org/0000-0001-5153-0149)
- Xiaopeng Zhou (ORCID: https://orcid.org/0000-0002-0650-183X)
- Xiaoyan Xu
- Xiaoyong Wu (ORCID: https://orcid.org/0000-0001-6781-3418)
- Bin Han (ORCID: https://orcid.org/0000-0002-7581-6202)
- Zheng Wei Yuan (ORCID: https://orcid.org/0000-0001-8588-9029)
Institutions
- Zhejiang Lab (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Research
- Published
- 2025-01-01
- DOI
- https://doi.org/10.34133/research.0957
- Citations
- 1
- Primary Topic
- Spine and Intervertebral Disc Pathology
- Type
- article
- Field-Weighted Citation Impact
- 1.47