Song Kangle, Gu Hanwen, Li Qi, Kong Xiangzhen, Li Yanlin, Meng Qunbo, Liu Kaiwen, Liu Zhenchuan, Wang Zexin, Zhang Yuanqiang, Xie Qing, Cheng Lei
Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, PR China.
Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, PR China.
Int J Biol Macromol. 2025 Sep;321(Pt 4):146457. doi: 10.1016/j.ijbiomac.2025.146457. Epub 2025 Jul 30.
Intervertebral disc degeneration (IVDD), driven by nucleus pulposus cell (NPCs) apoptosis, extracellular matrix (ECM) dyshomeostasis, and inflammation, lacks effective therapies. Lentinan (LNT), a polysaccharide from lentinula edodes, has anti-inflammatory and antioxidant properties. However, the role and molecular mechanisms of LNT in IVDD are unclear. In vitro, LNT counteracted IL-1β-induced NPCs apoptosis by restoring mitochondrial function, suppressing reactive oxygen species (ROS) accumulation, and rebalancing ECM metabolism via regulation of anabolic and catabolic markers. Mechanistic studies revealed that LNT enhanced autophagic flux by upregulating Suppressor of Cytokine Signaling 1 (SOCS1) expression, which inhibited Janus Kinase2 (JAK2) / Signal Transducer and Activator of Transcription 3 (STAT3) hyperactivation, thereby alleviating NPCs senescence and apoptosis under inflammation. Specifically, LNT downregulates histone deacetylase 6 (HDAC6), enhancing histone H3 lysine 27 acetylation (H3K27ac). This epigenetic modification promotes SOCS1 enhanced expression, which in turn suppresses the JAK2/STAT3 pathway, ultimately alleviating intervertebral disc degeneration. In vivo, LNT administration in a rat caudal IVDD model attenuated disc degeneration, as evidenced by preserved disc morphology, reduced ECM degradation. Immunohistochemical (IHC) and immunofluorescence (IF) experiments demonstrated that lentinan mediates the regulation of SOCS1 and restores the impaired autophagy status in rat tail intervertebral discs following puncture-induced injury. In human nucleus pulposus specimens, we have also identified the involvement of SOCS1/JAK2/STAT3 signaling in aged and degenerated nucleus pulposus. Consequently, LNT may be a promising candidate for the treatment of IVDD.
椎间盘退变（IVDD）由髓核细胞（NPCs）凋亡、细胞外基质（ECM）稳态失衡和炎症驱动，目前缺乏有效的治疗方法。香菇多糖（LNT）是一种从香菇中提取的多糖，具有抗炎和抗氧化特性。然而，LNT在IVDD中的作用和分子机制尚不清楚。在体外，LNT通过恢复线粒体功能、抑制活性氧（ROS）积累以及通过调节合成代谢和分解代谢标志物来重新平衡ECM代谢，从而抵消IL-1β诱导的NPCs凋亡。机制研究表明，LNT通过上调细胞因子信号转导抑制因子1（SOCS1）的表达来增强自噬通量，这抑制了Janus激酶2（JAK2）/信号转导和转录激活因子3（STAT3）的过度激活，从而减轻炎症条件下NPCs的衰老和凋亡。具体而言，LNT下调组蛋白去乙酰化酶6（HDAC6），增强组蛋白H3赖氨酸27乙酰化（H3K27ac）。这种表观遗传修饰促进SOCS1表达增强，进而抑制JAK2/STAT3途径，最终减轻椎间盘退变。在体内，在大鼠尾椎间盘退变模型中给予LNT可减轻椎间盘退变，椎间盘形态保存、ECM降解减少证明了这一点。免疫组织化学（IHC）和免疫荧光（IF）实验表明，香菇多糖介导SOCS1的调节，并恢复穿刺损伤后大鼠尾椎间盘受损的自噬状态。在人髓核标本中，我们还确定了SOCS1/JAK2/STAT3信号通路在老化和退变髓核中的作用。因此，LNT可能是治疗IVDD的有希望的候选药物。
