Salidroside alleviates MPP + -induced injury and mitochondrial fission in PC12 cells by mediating the HDAC6/MST1/MIEF1 axis

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the loss of dopaminergic neurons and impaired mitochondrial dynamics. Salidroside (SAL), a natural compound extracted from Rhodiola rosea, possesses antioxidative and anti-inflammatory properties, yet its role in regulating mitochondrial fission via specific molecular pathways in PD remains unclear. This study investigates the protective effects of SAL against MPP+-induced injury in PC12 cells and examines its mechanistic involvement in the HDAC6/MST1/MIEF1 axis. Using an MPP+-exposed PC12 cell model of PD-related cellular injury, we demonstrated that SAL treatment significantly restored cell viability, reduced Hoechst 33258-detected apoptotic nuclear changes, and reduced the concentrations of inflammatory cytokines in culture supernatants (IL-1β, IL-6, TNF-α). Furthermore, SAL attenuated oxidative stress by decreasing ROS and MDA levels while enhancing SOD activity. Importantly, SAL ameliorated mitochondrial dysfunction by improving membrane potential, increasing ATP production, and inhibiting fission protein expression (Drp1, Fis1, Mff). Mechanistic analyses revealed that SAL enhances HDAC6 promoter activity and increases HDAC6 protein expression; HDAC6 subsequently interacts with MST1 and regulates its acetylation status, while SAL treatment is associated with reduced MST1 and MIEF1 expression and suppression of mitochondrial fission signaling. The protective effects of SAL were nullified upon HDAC6 knockdown or overexpression of MST1/MIEF1, supporting the involvement of this signaling pathway in the protective effects of SAL. In conclusion, SAL mitigates MPP+-induced mitochondrial fission and cellular injury in PC12 cells through an HDAC6-dependent mechanism involving the MST1/MIEF1 axis, supporting further investigation of this pathway in more physiologically relevant PD models.