Salidroside (SAL) mitigates ferroptosis in Parkinson's disease (PD) by activating the Nrf2/GPX4 pathway. In a mouse model of PD induced by MPTP, SAL improved motor function, reduced α-synuclein expression, and increased tyrosine hydroxylase (TH) levels. It also enhanced antioxidant defenses, reduced malondialdehyde (MDA) and iron levels in the substantia nigra, and protected dopaminergic neurons. In vitro, SAL treatment of SH-SY5Y cells reduced ferroptosis markers, increased GPX4, Nrf2, and TH expression, and improved mitochondrial membrane potential. These effects were mediated through the Nrf2/GPX4 pathway, as shown by Western blot and immunofluorescence analyses. SAL's protective effects were reversed by Nrf2 inhibition, indicating the pathway's role in neuroprotection. The study highlights SAL's potential as a therapeutic agent for PD, targeting ferroptosis through the Nrf2/GPX4 pathway. Further research is needed to explore long-term effects, pharmacokinetics, and synergistic effects with existing PD treatments.Salidroside (SAL) mitigates ferroptosis in Parkinson's disease (PD) by activating the Nrf2/GPX4 pathway. In a mouse model of PD induced by MPTP, SAL improved motor function, reduced α-synuclein expression, and increased tyrosine hydroxylase (TH) levels. It also enhanced antioxidant defenses, reduced malondialdehyde (MDA) and iron levels in the substantia nigra, and protected dopaminergic neurons. In vitro, SAL treatment of SH-SY5Y cells reduced ferroptosis markers, increased GPX4, Nrf2, and TH expression, and improved mitochondrial membrane potential. These effects were mediated through the Nrf2/GPX4 pathway, as shown by Western blot and immunofluorescence analyses. SAL's protective effects were reversed by Nrf2 inhibition, indicating the pathway's role in neuroprotection. The study highlights SAL's potential as a therapeutic agent for PD, targeting ferroptosis through the Nrf2/GPX4 pathway. Further research is needed to explore long-term effects, pharmacokinetics, and synergistic effects with existing PD treatments.