2. Academic Validation
  3. Cryptotanshinone attenuates lactate-induced nucleus pulposus cells injury by modulating the STAT3/SIRT3 signaling axis

Cryptotanshinone attenuates lactate-induced nucleus pulposus cells injury by modulating the STAT3/SIRT3 signaling axis

  • Phytomedicine. 2025 Sep:145:157021. doi: 10.1016/j.phymed.2025.157021.
Jia-Jie Lu 1,  Qi-Chen Zhang 2,  Yi-Tuo Chen 1,  Guang-Cheng Yuan 1,  Yu-Kai Huang 1,  Tao Wu 1,  Qian-Yi Zhang 1,  Jian Dong 3,  Li-Bo Jiang 4,  Xi-Lei Li 5
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 2 Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Department of Orthopaedic Surgery, Xuhui Hospital, Fudan University, Shanghai, China.
  • 3 Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Department of Orthopaedic Surgery, Shanghai Baoshan District Wusong Center Hospital, Fudan University, Shanghai, 200940, China. Electronic address: dong.jian@zs-hospital.sh.cn.
  • 4 Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Department of Orthopaedic Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361000, China. Electronic address: jiang.libo@zs-hospital.sh.cn.
  • 5 Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. Electronic address: li.xilei@zs-hospital.sh.cn.
PMID: 40609385 DOI: 10.1016/j.phymed.2025.157021
Abstract

Introduction: Intervertebral disc degeneration (IVDD) stands out as one of the prevalent root causes of low back pain (LBP). In degenerated discs, the dysregulation of glucose metabolism and the impairment of nutrient transport result in the accumulation of lactate, which exacerbates oxidative stress in the microenvironment of the intervertebral disk thereby inducing senescence, Apoptosis and metabolic imbalance of the extracellular matrix in the nucleus pulposus cells (NPCs). In this context, elucidating the precise pathogenesis of disc degeneration and advancing the development of targeted molecular therapies hold significant therapeutic implications for future medical interventions.

Objective: The objective is to systematically evaluate small molecule compounds that influence intracellular oxidative stress and to elucidate their pharmacological effects and underlying molecular mechanisms.

Methods: The small molecule compound cryptotanshinone (Cry) was identified through a comprehensive literature, and the biosignature of the drug-disease target was subsequently analyzed utilizing network pharmacology methodologies. Subsequently, the pharmacological effects and molecular mechanisms of cryptotanshinone in the treatment of IVDD were investigated by ex vivo and in vivo experiments such as RNA-seq, Western blotting, immunofluorescence, SA-β-gal, Tunel, flow cytometry, immunohistochemistry, and animal imaging.

Results: In vitro findings demonstrated that Cry mitigates lactate-induced oxidative stress through modulation of the STAT3/SIRT3 signaling pathway, thereby reducing senescence, Apoptosis, and extracellular matrix (ECM) degradation in NPCs. Meanwhile, the outcomes of molecular docking and Surface plasmon resonance (SPR) analysis revealed that Cry exhibits a remarkable affinity towards STAT3. In a rat model of IVDD induced by needling, treatment with Cry significantly ameliorated the progression of IVDD.

Conclusions: To summarize, oxidative stress induced by lactate accumulation exhibits a strong correlation with the progression of IVDD. On this foundation, we obtained Cry by screening and demonstrated through mechanistic studies that it could attenuate lactate-induced injury to NPCs and thus improve IVDD, thus Cry may be a promising candidate for the treatment of IVDD.

Keywords

Cryptotanshinone; Lactate; Nucleus pulposus cell; Oxidative stress; STAT3/SIRT3.

Figures
Products