Small molecule natural compound agonist of SIRT3 as a therapeutic target for the treatment of intervertebral disc degeneration

Oxidative stress-induced mitochondrial dysfunction is implicated in the pathogenesis of intervertebral disc degeneration (IVDD). Sirtuin 3 (SIRT3), a sirtuin family protein located in mitochondria, is essential for mitochondrial homeostasis; however, the role of SIRT3 in the process of IVDD has remained elusive. Here, we explored the expression of SIRT3 in IVDD in vivo and in vitro; we also explored the role of SIRT3 in senescence, apoptosis, and mitochondrial homeostasis under oxidative stress. We subsequently activated SIRT3 using honokiol to evaluate its therapeutic potential for IVDD. We assessed SIRT3 expression in degenerative nucleus pulposus (NP) tissues and oxidative stress-induced nucleus pulposus cells (NPCs). SIRT3 was knocked down by lentivirus and activated by honokiol to determine its role in oxidative stress-induced NPCs. The mechanism by which honokiol affected SIRT3 regulation was investigated in vitro, and the therapeutic potential of honokiol was assessed in vitro and in vivo. We found that the expression of SIRT3 decreased with IVDD, and SIRT3 knockdown reduced the tolerance of NPCs to oxidative stress. Honokiol (10 μM) improved the viability of NPCs under oxidative stress and promoted their properties of anti-oxidation, mitochondrial dynamics and mitophagy in a SIRT3-dependent manner. Furthermore, honokiol activated SIRT3 through the AMPK-PGC-1α signaling pathway. Moreover, honokiol treatment ameliorated IVDD in rats. Our study indicated that SIRT3 is involved in IVDD and showed the potential of the SIRT3 agonist honokiol for the treatment of IVDD. Molecules that counteract metabolic abnormalities in spinal tissue could help treat lower back pain associated with disc degeneration. In this condition, the cells that form the discs experience heightened oxidative stress, wherein mitochondria produce high levels of toxic compounds. Researchers in China led by Xiangyang Wang of the Second Affiliated Hospital of Wenzhou Medical University and Xiaolei Zhang of the Zhejiang Provincial Key Laboratory of Orthopedics have identified a molecular target that may enable doctors to prevent this damage. They determined that a protein called SIRT3 plays a critical role in mitigating oxidative stress, and that its loss renders stressed disc tissue especially vulnerable. The researchers also found that honokiol—a SIRT3-activating compound derived from magnolia tree bark—effectively prevents disc degeneration in rats. A similar treatment strategy could potentially prove beneficial in human patients.