• Salidroside activates the SIRT1/FOXO3 pathway to enhance mitophagy in NPMSCs, counteracting mitochondrial dysfunction and oxidative stress in intervertebral disc degeneration.
• Network pharmacology and molecular dynamics identified SIRT1 as a direct target of salidroside, providing a mechanistic basis for its protective effects.
• In vitro and in vivo experiments demonstrate that salidroside preserves disc height, reduces apoptosis, and promotes mitophagic flux, while SIRT1 knockdown or autophagy inhibition abolishes these benefits.
• This study highlights salidroside as a promising therapeutic candidate for IVDD by awakening endogenous repair mechanisms in NPMSCs.