Mitigating nucleus pulposus cell senescence in intervertebral disk degeneration: the role of nodakenin in SIRT6 and PINK1/Parkin-associated mitophagy signaling

Intervertebral disc degeneration (IVDD) is a common and challenging chronic condition in orthopedics, primarily characterized by the aging of nucleus pulposus cells (NPC). Current treatment strategies for IVDD, particularly those targeting NPC senescence, remain underdeveloped. Research has shown that NPC senescence is closely associated with mitochondrial damage, leading to the accumulation of cytoplasmic reactive oxygen species (ROS) and mitochondrial DNA (mtDNA). Mitochondrial autophagy, as a key mechanism of mitochondrial quality control, regulates ROS and mtDNA levels by eliminating dysfunctional and damaged mitochondria, thereby delaying cellular aging. Notably, mitophagy signaling associated with Sirtuin 6 (SIRT6) and PTEN-induced kinase 1 (PINK1)/Parkin has been implicated in this process. Traditional Chinese Medicine (TCM), with its holistic approach and unique theoretical system of syndrome differentiation and treatment, offers significant advantages in preventing and treating degenerative diseases such as IVDD. However, research into TCM formulations aimed at NPC senescence remains limited. In preliminary studies, we observed that Nodakenin, the primary active compound from the TCM formula Duhuo Jisheng decoction (DHJSD), exerts protective effects in a SIRT6-associated manner and appears to be associated with activation of PINK1/Parkin-related mitophagy signaling. In this study, we used single-cell analysis to construct human NPC senescence and rat IVDD models, assessing mitochondrial morphology, mitochondrial membrane potential, cell senescence, and autophagy-related gene expression. We further evaluated the effects of Nodakenin (Nod) on H 2 O 2 -induced NPC senescence and determined the optimal intervention concentration, followed by assessment of mitochondrial phenotypes and SIRT6- and PINK1/Parkin-associated markers. These findings provide new theoretical support for the clinical application of TCM in the treatment of IVDD.