Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Integrating thermal proteome profiling and virtual screening to reveal the mechanism of Bletilla striata against osteoclast-driven osteoporosis.
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Dai Guiyu, Yang Ying, Mu Wen, Li Yanfang, Tu Yanbei
Аннотация
BACKGROUND: Osteoclast (OC) overactivation and increased bone resorption are central factors contributing to osteoporosis (OP). Bletilla striata (Thunb.) Reichb. f. is known for its hemostatic properties, however, its therapeutic potential and underlying mechanisms in OC-dependent OP remain unclear.
PURPOSE: This study aimed to evaluate the anti-OP effects of Bletilla striata extract (BSE) and elucidate its mechanisms of action (MoAs) through an innovative integrated strategy combining isothermal thermal proteome profiling (TPP) and structure-based virtual screening (SBVS).
RESULTS: BSE treatment significantly decreased bone loss in ovariectomized rats, as evidenced by micro-CT and pathological analyses. This effect was attributed to inhibition of OC formation by BSE. BSE markedly blocked RANKL-induced OC differentiation, inhibited F-actin ring formation, and decreased the expression of marker genes and proteins including NFATc1, CTSK, and MMP-9. Using an isothermal TPP strategy, 110 proteins were identified as the direct targets of BSE for OC inhibition based on proteome-level thermal stability analysis (fold change > 2.0). Subsequently, using label-free quantitative proteomics, 159 proteins were identified as indirect response proteins resulting from the interaction between BSE and direct targets. The SBVS approach was employed to establish a one-to-one correspondence between the chemical ingredients in BSE and the direct targets revealed by isothermal TPP. Based on these data, an "active ingredient-direct target-indirect response signal" interaction network was constructed, which revealed the key targets (ATM, PIK3R1, BUB1B, and NR3C1) and active ingredients (phenanthrene dimers and steroids) of BSE responsible for inhibiting OC formation.
CONCLUSION: This study not only highlights the therapeutic potential of BSE for treating OP but also provides a novel methodological framework for interpreting the MoAs of complex Traditional Chinese Medicine (TCM) extracts. By integrating isothermal TPP and SBVS, this study offers new insights into the mechanism of TCM.
PURPOSE: This study aimed to evaluate the anti-OP effects of Bletilla striata extract (BSE) and elucidate its mechanisms of action (MoAs) through an innovative integrated strategy combining isothermal thermal proteome profiling (TPP) and structure-based virtual screening (SBVS).
RESULTS: BSE treatment significantly decreased bone loss in ovariectomized rats, as evidenced by micro-CT and pathological analyses. This effect was attributed to inhibition of OC formation by BSE. BSE markedly blocked RANKL-induced OC differentiation, inhibited F-actin ring formation, and decreased the expression of marker genes and proteins including NFATc1, CTSK, and MMP-9. Using an isothermal TPP strategy, 110 proteins were identified as the direct targets of BSE for OC inhibition based on proteome-level thermal stability analysis (fold change > 2.0). Subsequently, using label-free quantitative proteomics, 159 proteins were identified as indirect response proteins resulting from the interaction between BSE and direct targets. The SBVS approach was employed to establish a one-to-one correspondence between the chemical ingredients in BSE and the direct targets revealed by isothermal TPP. Based on these data, an "active ingredient-direct target-indirect response signal" interaction network was constructed, which revealed the key targets (ATM, PIK3R1, BUB1B, and NR3C1) and active ingredients (phenanthrene dimers and steroids) of BSE responsible for inhibiting OC formation.
CONCLUSION: This study not only highlights the therapeutic potential of BSE for treating OP but also provides a novel methodological framework for interpreting the MoAs of complex Traditional Chinese Medicine (TCM) extracts. By integrating isothermal TPP and SBVS, this study offers new insights into the mechanism of TCM.