Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder globally, impacting an estimated 6 million individuals worldwide [1]. It is characterized by midbrain dopaminergic neuron loss and dopamine deficiency, which manifest in the form motor symptoms (bradykinesia, rigidity, tremor) and non-motor symptoms (cognitive decline, autonomic dysfunction, sleep disorders) [2,3]. PD pathogenesis involves many factors, including oxidative stress, α-synuclein aggregation, lysosomal dysfunction, iron dyshomeostasis-linked ferroptosis, and neuroinflammation [4]. Due to the intricate pathogenesis of PD, no definitive treatment exists, and the predominant therapeutic strategy focuses on alleviating symptoms and complications. Therapy mostly relies on dopamine replacement with medicines such as levodopa [5]. Consequently, this therapeutic gap underscores the critical need for novel pharmacological interventions targeting PD-specific pathways.

Iron is an essential element for mitochondrial function, neuronal development, and the maintenance of cognitive function. Excessive iron, however, results in organismal malfunction [6]. Ferroptosis, also termed “iron death,” refers to a type of programmed cell death initially reported by Dixon and colleagues in 2012. Marked by iron reliance, it has unique cellular morphological and genetic traits that differentiate it from apoptosis, necrosis, and autophagy [7]. Abnormal accumulation of iron plays a crucial role in the mechanism of ferroptosis. Excessive iron generates reactive oxygen species (ROS) through the Fenton reaction [8]. The resultant ROS interact with polyunsaturated fatty acids in plasma and organelle membranes, leading to lipid peroxidation and facilitating the onset of ferroptosis [9]. Furthermore, the dysregulation of the classical system Xc− (cystine/glutamate antiporter)-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, which is the primary antioxidant system, significantly contributes to ferroptosis. Generally, the system Xc−-GSH-GPX4 axis utilizes GSH to transform toxic lipid hydroperoxides into non-toxic lipid alcohols. When the axis is compromised, ferroptosis intensifies [10,11].

Emerging evidence highlights ferroptosis as a key contributor to neurodegenerative disease progression, particularly in PD [12]. PD and ferroptosis share many similar pathological features, including oxidative stress, iron deposition, a reduction of GSH levels, and lipid peroxidation, all of which promote the onset of PD while advancing the process of ferroptosis [13]. Autopsy and magnetic resonance imaging studies have confirmed elevated levels of total and non-heme iron in the substantia nigra of patients with PD [14]. Furthermore, ferroptosis has been shown to exacerbate neurodegeneration in PD models induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), or rotenone, whereas the pharmacological inhibition of ferroptosis alleviates motor deficits and neuronal loss [[15], [16], [17]]. This suggests that ferroptosis inhibitors may have therapeutic potential in PD treatment. Some researchers have employed the use of deferiprone (DFP, an iron-chelating agent) in the treatment of PD, observing that it reduces iron depositions in the substantia nigra, putamen, and other brain regions associated with PD progression. The therapeutic efficacy of this method remains ambiguous, thus hindering its clinical application [18]. As a result, there is an increased need to address PD by developing pharmacological agents capable of inhibiting ferroptosis.

Moschus, a traditional Chinese medicine derived from male musk deer's gland secretions, contains muscone as its primary bioactive compound, with pharmacological effects comparable to natural musk [19]. The literature indicates that muscone possesses notable anti-inflammatory, antioxidant, and anti-apoptotic properties, as well as the capacity to modulate autophagy [[20], [21], [22]]. Given its numerous benefits, muscone has been used to enhance cardiac function, induce anti-tumor responses, and facilitate hypnotic and analgesic effects [[23], [24], [25]]. Most notably, muscone has demonstrated neuroprotective effects in various disease models, including cerebral ischemic stroke, Alzheimer's disease, and diabetic peripheral neuropathy [21,22,26], yet its role in PD remains uncharted. A recent study demonstrated that Moschus water extract attenuates erastin-induced ferroptosis in HT22 cells (a murine hippocampal neuronal line), suggesting a potential anti-ferroptotic role of its components, though the specific contribution of muscone remains uncharacterized [27].

Our study aimed to validate the idea that muscone, as the primary active compound in Moschus, can provide a protective effect against PD by mitigating ferroptosis. We found that muscone alleviates ferroptosis in MPTP/1-methyl-4-phenylpyridinium ion (MPP+)-induced PD cell and animal models by inhibiting glycogen synthase kinase 3β (GSK-3β), with GSK-3β exhibiting a significant association between PD and ferroptosis [28,29]. Our results offer a traditional Chinese medicine-based therapeutic approach for the management of PD.