2. Academic Validation
  3. Sophoraflavanone G as an ectosteric inhibitor of cathepsin K attenuates ovariectomy-induced bone loss by suppressing bone resorption

Sophoraflavanone G as an ectosteric inhibitor of cathepsin K attenuates ovariectomy-induced bone loss by suppressing bone resorption

  • Phytomedicine. 2025 Jun:141:156720. doi: 10.1016/j.phymed.2025.156720.
Xueling Hu 1,  Chunxia Liu 2,  Ziling Tang 1,  Mingyu Pan 3,  Ailing Fang 1,  Ling Li 4,  Xiangbo Meng 4,  Xiyang Tang 2,  Yanzhi Liu 5,  Xinluan Wang 4,  Hao Gao 2,  Jian Zou 6,  Zuocheng Qiu 7
Affiliations

Affiliations

  • 1 Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, School of Traditional Chinese Medicine/ Jinan University, Guangzhou 510632, China.
  • 2 Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education of China, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China.
  • 3 State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China.
  • 4 Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518057, China.
  • 5 Shenzhen Osteomore Biotechnology Co., Ltd., Shenzhen 518118, China.
  • 6 Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education of China, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China. Electronic address: zoujian@jnu.edu.cn.
  • 7 Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, School of Traditional Chinese Medicine/ Jinan University, Guangzhou 510632, China. Electronic address: zcqiu@jnu.edu.cn.
PMID: 40220429 DOI: 10.1016/j.phymed.2025.156720
Abstract

Background: Cathepsin K (CTSK) is a key enzyme in bone resorption, making it a promising target for osteoporosis treatment. Active-site inhibitors of CTSK are effective but have undesirable side effects, while ectosteric inhibitors may provide a safer alternative.

Purpose: This study investigates whether Sophoraflavanone G (SG), derived from Rhizoma Drynariae, can act as an ectosteric CTSK inhibitor to attenuate osteoporotic bone loss and explores its underlying mechanisms.

Study design: SG's effects were evaluated in an ovariectomized (OVX) osteoporotic mice model, with in vitro experiments assessing SG's interaction and binding affinity with CTSK.

Methods: Micro-CT, histology, and mechanical testing were used to evaluate bone density and strength. CTSK activity and expression were assessed by immunohistochemistry and western blotting. Cell thermal shift assays, isothermal titration calorimetry, CTSK site-specific degradation assays, molecular docking and dynamic simulation were performed to study SG's binding affinity and inhibitory effects. Biosafety, including body weight, uterine histomorphometry, and toxicity of the heart and lung, was also assessed.

Results: SG improved bone mineral density, microarchitecture, and strength, primarily by inhibiting bone resorption. It inhibited CTSK's enzymatic activity with a strong binding affinity (KD: 8.49 μM) and effectively inhibited osteoclast function. CTSK site-specific assays showed SG inhibited CTSK-mediated degradation of type I Collagen. Unlike odanacatib, SG did not affect gelatin or TGF-β1 degradation in fibroblasts. Biosafety assessments revealed no adverse effects.

Conclusion: SG acts as an ectosteric CTSK inhibitor, offering a safer alternative for postmenopausal osteoporosis treatment by selectively inhibiting bone resorption without the side effects associated with active-site inhibitors.

Keywords

Bone resorption; Cathepsin K; Collagenase inhibition; Ectosteric inhibitor; Osteoporosis; Sophoraflavanone G.

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