2. Academic Validation
  3. Sinensetin serves as an AMPK activator to inhibit RANKL-induced osteoclastogenesis via osteoclast cytoskeleton reorganization

Sinensetin serves as an AMPK activator to inhibit RANKL-induced osteoclastogenesis via osteoclast cytoskeleton reorganization

  • J Transl Med. 2025 Jul 18;23(1):805. doi: 10.1186/s12967-025-06708-8.
Yijie Gao # 1 2 3,  Rui Zhou # 1 2,  Xixi Lin # 4,  Zhijuan Liu 1 2,  Yuangang Su 1,  Haoyu Lian 1,  Bin Lin 4,  Xiaofei Ding 1 2,  Shijie Liao 1 2,  Xiangde Li 1,  Jinmin Zhao 1 2,  Jiake Xu 5 6,  Ren Xu 7,  Qian Liu 8,  Fangming Song 9 10 11
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of Regenerative Medicine, Orthopaedics Trauma and Hand Surgery, the First Affiliated Hospital of Guangxi Medical University, 22 Shuangyong Road, Nanning, 530000, China.
  • 2 Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed By the Province and Ministry, Guangxi Medical University, Nanning, 530000, China.
  • 3 The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, China.
  • 4 Department of Orthopedic Surgery, The 909 Hospital, School of Medicine, Xiamen University, 269 Zhanghua Middle Road, Zhangzhou, 363000, China.
  • 5 School of Biomedical Sciences, the University of Western Australia, Perth, Australia.
  • 6 Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518000, China.
  • 7 Department of Orthopedic Surgery, The 909 Hospital, School of Medicine, Xiamen University, 269 Zhanghua Middle Road, Zhangzhou, 363000, China. xuren526@xmu.edu.cn.
  • 8 Guangxi Key Laboratory of Regenerative Medicine, Orthopaedics Trauma and Hand Surgery, the First Affiliated Hospital of Guangxi Medical University, 22 Shuangyong Road, Nanning, 530000, China. liuqian@gxmu.edu.cn.
  • 9 Guangxi Key Laboratory of Regenerative Medicine, Orthopaedics Trauma and Hand Surgery, the First Affiliated Hospital of Guangxi Medical University, 22 Shuangyong Road, Nanning, 530000, China. songfangming@gxmu.edu.cn.
  • 10 Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed By the Province and Ministry, Guangxi Medical University, Nanning, 530000, China. songfangming@gxmu.edu.cn.
  • 11 Life Sciences Institute, Guangxi Medical University, Nanning, 530021, China. songfangming@gxmu.edu.cn.
  • # Contributed equally.
PMID: 40682116 DOI: 10.1186/s12967-025-06708-8
Abstract

Osteoporosis is a skeletal condition caused by an excess of osteoclasts, resulting in an imbalance in bone metabolism. Sinensetin (SIN), one of the main ingredients in citrus fruits, provides a variety of pharmacological properties, like antioxidant, but its effects on osteoporosis remains unknown. Herein, we explored at how SIN affected RANKL-induced osteoclastogenesis and ovariectomy (OVX)-induced osteoporotic mice. Our research found that SIN, without compromising cell viability, inhibited RANKL-mediated osteoclastogenesis and the NFATc1 signaling pathway in a concentration-dependent manner. Further, RNA Sequencing analysis suggested that the molecular mechanism of SIN inhibitory effect on osteoclasts is related to the Cytoskeleton reorganization. The results indicated that SIN prevents the Cytoskeleton reorganization of preosteoclasts via the c-Src-mediated PI3K/PAK4/Akt signaling axis. Meanwhile, SIN enhanced the expression of phosphorylation and activity of AMP-activated protein kinase (AMPK) in response to RANKL. Further, SIN targets AMPK to reduce intracellular Reactive Oxygen Species (ROS) levels, thereby blocking c-Src activation. Finally, we verified that SIN inhibits osteoclast activity, thus preventing OVX-induced bone loss. These findings suggest that SIN serves as an AMPK Activator that abrogates RANKL-induced osteoclastogenesis and OVX-induced bone loss via hindering Cytoskeleton reorganization.

Keywords

AMPK; Cytoskeleton reorganization; Osteoclast; ROS; Sinensetin.

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