β-Mangostin Attenuates TET2-Mediated DNA Demethylation of Prkcg in the Prevention of Intervertebral Disc Degeneration

Xiangzhen Kong; Hanwen Gu; Yuanqiang Zhang; Qunbo Meng; Qi Li; Kangle Song; Yanlin Li; Kaiwen Liu; Zhenchuan Liu; Rui Hu; Haoxi Zhai; Tian Li; Zemin Ling; Zhijian Wei; Fuxin Wei; Lei Cheng

doi:10.1002/advs.202505077

β-Mangostin Attenuates TET2-Mediated DNA Demethylation of Prkcg in the Prevention of Intervertebral Disc Degeneration

Adv Sci (Weinh). 2025 Jun 25:e05077. doi: 10.1002/advs.202505077. Online ahead of print.

Authors

Xiangzhen Kong^{1

2}, Hanwen Gu^{1

2}, Yuanqiang Zhang^{1

2}, Qunbo Meng^{1

2}, Qi Li^{1

2}, Kangle Song^{1

2}, Yanlin Li^{1

2}, Kaiwen Liu^{1

2}, Zhenchuan Liu^{1

2}, Rui Hu^{1

2}, Haoxi Zhai^{1

2}, Tian Li³, Zemin Ling⁴, Zhijian Wei^{5

6

7}, Fuxin Wei⁴, Lei Cheng^{1

2}

Affiliations

¹ Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, P. R. China.
² The First Clinical College of Shandong University, Jinan, Shandong, 250012, P. R. China.
³ Tianjin Key Laboratory of Acute Abdomen Disease-Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, 8 Changjiang Avenue, Tianjin, 300100, P. R. China.
⁴ Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, P. R. China.
⁵ Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Shandong University, No. 107 Wenhua West Road, Lixia District, Jinan, 250012, P. R. China.
⁶ Department of Orthopaedics, The Second Hospital of Shandong University, No. 247 Beiyuan Street, Tianqiao District, Jinan, 250033, P. R. China.
⁷ Department of Orthopedics, Tianjin Medical University General Hospital, International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, No. 154 Anshan Road, Heping District, Tianjin, 300052, P. R. China.

PMID: 40558107
DOI: 10.1002/advs.202505077

Abstract

Intervertebral disc degeneration (IDD) induced lower back pain is a main cause of disability, resulting in a substantial workforce loss worldwide and placing a substantial burden on the global economy and healthcare systems. However, no effective disease-modifying therapies presently exist for IDD or its related pathologies. Single-cell sequencing analyses reveal progressive M1 macrophage polarization in NP cells correlating with IDD severity, underscoring the therapeutic imperative for dual-targeting agents addressing both inflammatory dysregulation and matrix homeostasis. β-mangostin (β_Man) is screened to be proven to possess potential therapeutic effects in alleviating IDD. β_Man possesses anti-inflammatory capabilities, which include remodeling the homeostasis of the extracellular matrix, regulating macrophage polarization, and inhibiting apoptosis in the nucleus pulposus. TET2-Prkcg exerts significant regulatory functions downstream of β_Man. Mechanically, β_Man mediated reduction of TET2 maintains the DNA methylation of Prkcg rather than hydroxymethylation, which promotes mitophagy and alleviates the inflammatory microenvironment. β_Man represents a promising novel therapeutic strategy for IDD treatment. The TET2-Prkcg axis emerges as a novel therapeutic target for IDD treatment.

Keywords: Prkcg; TET2; demethylation; intervertebral disc degeneration; β‐mangostin.

Abstract

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