Intervertebral disc degeneration (IVDD) is a prevalent degenerative disease with significant adverse implications for patients' quality of life and socioeconomic status. Although the precise etiology of IVDD remains elusive, the senescence of nucleus pulposus cells is recognized as the primary pathogenic factor of IVDD; however, drugs that may targetedly inhibit senescence are still lacking. In the current study, we evaluated the small-molecule active drug 20-Deoxyingenol(20-DOI) for its effects on combating senescence and delaying the progression of IVDD. In vitro experiments revealed that the administration of 20-DOI displayed inhibitory effects on senescence and the senescence-related cGAS-STING pathway of nucleus pulposus cells. Additionally, it exhibited the ability to enhance lysosome activity and promote autophagy flux within nucleus pulposus cells. Subsequent investigations elucidated that the inhibitory impact of 20-DOI on nucleus pulposus cell senescence was mediated through the autophagy-lysosome pathway. This effect was diminished in the presence of transcription factor EB (TFEB) small hairpin RNA (shRNA), thereby confirming the regulatory role of 20-DOI on the autophagy-lysosome pathway and senescence through TFEB. In vivo experiments demonstrated that 20-DOI effectively impeded the progression ofIVDD in rats. These findings collectively illustrate that 20-DOI may facilitate the autophagy-lysosomal pathway by activating TFEB, thereby suppressing the senescence in nucleus pulposus cells, thus suggesting 20-DOI as a promising therapeutic approach for IVDD.

椎间盘退变（IVDD）是一种普遍的退行性疾病，对患者的生活质量和社会经济状况产生重大不利影响。尽管IVDD的确切病因仍不清楚，但髓核细胞的衰老被认为是IVDD的主要致病因素。然而，目前仍然缺乏可以靶向抑制衰老的药物。在本研究中，我们评估了小分子活性药物 20-Deoxyingenol (20-DOI) 对抗衰老和延缓 IVDD 进展的作用。体外实验表明，给予20-DOI对髓核细胞的衰老和衰老相关的cGAS-STING通路具有抑制作用。此外，它还表现出增强溶酶体活性并促进髓核细胞内自噬通量的能力。随后的研究阐明20-DOI对髓核细胞衰老的抑制作用是通过自噬-溶酶体途径介导的。当转录因子 EB (TFEB) 小发夹 RNA (shRNA) 存在时，这种效应会减弱，从而证实了 20-DOI 通过 TFEB 对自噬-溶酶体途径和衰老的调节作用。体内实验表明，20-DOI 可有效阻止大鼠 IVDD 的进展。这些发现共同表明20-DOI可能通过激活TFEB促进自噬-溶酶体途径，从而抑制髓核细胞的衰老，从而表明20-DOI是一种有前景的IVDD治疗方法。