Temporal interference stimulation rescues dopaminergic neurons in the substantia nigra of MPTP-induced Parkinson’s disease mice via inhibition of lipid peroxidation

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). Currently, there is a lack of effective therapies to slow disease progression. Temporal interference (TI) stimulation, as a novel non‑invasive neuromodulation technique, can generate a focused electric field in deep brain regions; however, whether it can effectively act on the SN and influence PD-related pathological processes remains unclear. To investigate the neuroprotective effects of TI stimulation on dopaminergic neurons in the SN of MPTP mice and explore the potential mechanisms involved. After establishing a subacute MPTP model, TI stimulation with a 10 Hz beat frequency was applied to the SN of mice for five consecutive days. Therapeutic outcomes and molecular mechanisms were evaluated using behavioral tests, immunohistochemistry, Western blot, transcriptome sequencing, untargeted lipidomics, and primary neuronal culture experiments. TI stimulation significantly improved motor function in MPTP mice, increased the number of TH‑positive neurons in the SN, and attenuated glial activation and neuroinflammation. Integrated transcriptomic and lipidomic analyses revealed that TI intervention downregulated PLA2G3. Experimentally, TI reduced the expression of ACSL4, upregulated GPX4, decreased MDA levels, elevated reduced GSH levels, and suppressed lipid peroxidation. In vitro experiments further confirmed that TI reduced MPP⁺‑induced primary neuronal death and lipid peroxidation accumulation. TI stimulation protects nigral dopaminergic neurons by inhibiting lipid peroxidation, ameliorates motor deficits and pathological features in PD mice, and provides a novel strategy for non‑invasive neuromodulation therapy in PD. Not applicable.