Cheng Zhangrong, Gao Haiyang, Shi Pengzhi, Zhang Anran, Chen Xianglong, Chen Yuhang, Gan Weikang, Zhao Kangcheng, Li Shuai, Yang Cao, Zhang Yukun
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Bone Res. 2025 Jun 12;13(1):62. doi: 10.1038/s41413-025-00441-0.
Intervertebral disc degeneration (IDD) is a progressive and dynamic process in which the senescence-associated secretory phenotype (SASP) of nucleus pulposus cells (NPC) plays a significant role. While impaired chaperone-mediated autophagy (CMA) has been associated with inflammation and cellular senescence, its specific involvement in the self-perpetuating feedback loop of NPC senescence remains poorly understood. Through LAMP2A knockout in NPC, we identified a significant upregulation of DYRK1A, a core mediator of premature senescence in Down syndrome. Subsequent validation established DYRK1A as the critical driver of premature senescence in CMA-deficient NPC. Combinatorial transcription factor analysis revealed that under IL1B stimulation or CMA inhibition, elevated DYRK1A promoted FOXC1 phosphorylation and nuclear translocation, initiating transcriptional activation of cell cycle arrest. Intriguingly, CMA impairment concurrently enhanced glutamine metabolic flux in senescent NPC, thereby augmenting their survival fitness. Transcriptomic profiling demonstrated that CMA reactivation in senescent NPC facilitated fate transition from senescence to apoptosis, mediated by decreased glutamine flux via GLUL degradation. Therefore, CMA exerts protective effects against IDD by maintaining equilibrium between premature senescence and senolysis. This study elucidates CMA's regulatory role in SASP-mediated senescence amplification circuits, providing novel therapeutic insights for IDD and other age-related pathologies.
椎间盘退变（IDD）是一个渐进性的动态过程，其中髓核细胞（NPC）的衰老相关分泌表型（SASP）起着重要作用。虽然伴侣介导的自噬（CMA）受损与炎症和细胞衰老有关，但其在NPC衰老的自我延续反馈回路中的具体作用仍知之甚少。通过在NPC中敲除LAMP2A，我们发现唐氏综合征中过早衰老的核心介质DYRK1A显著上调。随后的验证确定DYRK1A是CMA缺陷型NPC过早衰老的关键驱动因素。组合转录因子分析表明，在IL1B刺激或CMA抑制下，升高的DYRK1A促进FOXC1磷酸化和核转位，启动细胞周期停滞的转录激活。有趣的是，CMA损伤同时增强了衰老NPC中的谷氨酰胺代谢通量，从而提高了它们的生存适应性。转录组分析表明，衰老NPC中CMA的重新激活促进了从衰老到凋亡的命运转变，这是由通过GLUL降解减少谷氨酰胺通量介导的。因此，CMA通过维持过早衰老和衰老溶解之间的平衡对IDD发挥保护作用。本研究阐明了CMA在SASP介导的衰老放大回路中的调节作用，为IDD和其他与年龄相关的疾病提供了新的治疗思路。
