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Updated: Jun 2, 2025
Author Spotlight: Integrating Mechanical and Biological Analysis in Tendinopathy Research
Published on: March 1, 2024
Sirolimus as a repurposed drug for tendinopathy: A systems biology approach combining computational and experimental
Zetao Wang1, Junchao Luo2, Luyong Jiang3
1Department of Orthopedics, Affiliated Huzhou Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Huzhou, China; Department of Sports Medicine & Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of sports medicine, Zhejiang University, Hangzhou, China; Orthopedics Research Institute of Zhejiang University, Hangzhou, China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, China; Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, China.
Background:
Effective drugs for tendinopathy are lacking, resulting in significant morbidity and re-tearing rate after operation. Applying systems biology to identify new applications for current pharmaceuticals can decrease the duration, expenses, and likelihood of failure associated with the development of new drugs.
Methods:
We identify tendinopathy signature genes employing a transcriptomics database encompassing 154 clinical tendon samples. We then proposed a systems biology based drug prediction strategy that encompassed multiplex transcriptional drug prediction, systematic review assessment, deep learning based efficacy prediction and Mendelian randomization (MR). Finally, we evaluated the effects of drug target using gene knockout mice.
Results:
We demonstrate that sirolimus is a repurposable drug for tendinopathy, supported by: 1) Sirolimus achieves top ranking in drug-gene signature-based multiplex transcriptional drug efficacy prediction, 2) Consistent evidence from systematic review substantiates the efficacy of sirolimus in the management of tendinopathy, 3) Genetic prediction indicates that plasma proteins inhibited by mTOR (the target of sirolimus) are associated with increased tendinopathy risk. The effectiveness of sirolimus is further corroborated through in vivo testing utilizing tendon tissue-specific mTOR gene knockout mice. Integrative pathway enrichment analysis suggests that mTOR inhibition can regulate heterotopic ossification-related pathways to ameliorate clinical tendinopathy.
Conclusions:
Our study assimilates knowledge of system-level responses to identify potential drugs for tendinopathy, and suggests sirolimus as a viable candidate. A systems biology approach could expedite the repurposing of drugs for human diseases that do not have well-defined targets.
