Lu Jia-Jie, Zhang Qi-Chen, Chen Yi-Tuo, Yuan Guang-Cheng, Huang Yu-Kai, Wu Tao, Zhang Qian-Yi, Dong Jian, Jiang Li-Bo, Li Xi-Lei
Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Department of Orthopaedic Surgery, Xuhui Hospital, Fudan University, Shanghai, China.
Phytomedicine. 2025 Jun 28;145:157021. doi: 10.1016/j.phymed.2025.157021.
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.
The objective is to systematically evaluate small molecule compounds that influence intracellular oxidative stress and to elucidate their pharmacological effects and underlying molecular mechanisms.
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.
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.
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.
椎间盘退变（IVDD）是腰痛（LBP）的常见根源之一。在退变的椎间盘中，葡萄糖代谢失调和营养物质运输受损导致乳酸积累，这加剧了椎间盘微环境中的氧化应激，从而诱导髓核细胞（NPCs）衰老、凋亡和细胞外基质代谢失衡。在此背景下，阐明椎间盘退变的确切发病机制并推动靶向分子疗法的发展对未来医学干预具有重要的治疗意义。
旨在系统评估影响细胞内氧化应激的小分子化合物，并阐明其药理作用及潜在分子机制。
通过综合文献筛选出小分子化合物隐丹参酮（Cry），随后利用网络药理学方法分析药物-疾病靶点的生物特征。随后，通过RNA测序、蛋白质免疫印迹、免疫荧光、SA-β-半乳糖苷酶染色、TUNEL检测、流式细胞术、免疫组化和动物成像等体外和体内实验研究隐丹参酮治疗IVDD的药理作用和分子机制。
体外研究结果表明，Cry通过调节STAT3/SIRT3信号通路减轻乳酸诱导的氧化应激，从而减少NPCs的衰老、凋亡和细胞外基质（ECM）降解。同时，分子对接和表面等离子体共振（SPR）分析结果显示，Cry对STAT3具有显著亲和力。在针刺诱导的IVDD大鼠模型中，Cry治疗显著改善了IVDD的进展。
综上所述，乳酸积累诱导的氧化应激与IVDD的进展密切相关。在此基础上，我们通过筛选获得了Cry，并通过机制研究证明其可减轻乳酸对NPCs的损伤，从而改善IVDD，因此Cry可能是治疗IVDD的有前景的候选药物。
