• Salidroside activates the SIRT1/FOXO3 signaling pathway to enhance mitophagy in nucleus pulposus-derived mesenchymal stem cells (NPMSCs), thereby mitigating oxidative stress-induced mitochondrial dysfunction and apoptosis.
• Network pharmacology, molecular docking, and dynamics simulations identified SIRT1 as a direct molecular target of salidroside, with stable binding confirmed experimentally.
• In vitro, salidroside treatment restored mitophagic flux, reduced reactive oxygen species accumulation, and suppressed apoptosis in TBHP-treated NPMSCs; these effects were abolished by SIRT1 knockdown or autophagy inhibition with 3-MA.
• In a rat model of intervertebral disc degeneration, salidroside preserved disc height, reduced apoptosis, and enhanced mitophagy, while 3-MA exacerbated degeneration, supporting the therapeutic potential of targeting the SIRT1/FOXO3-mitophagy axis.