Parkinson's disease (PD) stands as the second most widespread neurological disorder worldwide, marked by the degeneration and depletion of dopaminergic neurons within the substantia nigra [1]. The primary clinical manifestations of PD include slow movement, muscular rigidity, and resting tremor. Furthermore, non-motor symptoms associated with PD include cognitive disorders, sleep disturbances, and autonomic dysfunction [2]. The intricate pathogenesis of PD involves mitochondrial dysfunction, dysregulation of dopamine homeostasis, neuroinflammation, and autophagy [3]. Owing to the intricate pathogenesis and diverse clinical manifestations of PD, diagnosing and treating the condition remains a formidable challenge. Contemporary Western medicine primarily employs drug therapy and later-stage deep brain stimulation; however, these interventions can only manage symptoms to a certain extent and fail to decelerate disease progression, often resulting in adverse reactions [4,5]. Therefore, a comprehensive comprehension of the pathogenesis of PD is essential, requiring the formulation of innovative therapeutic approaches based on this comprehension to hinder or postpone the advancement of the disorder.

It is worth highlighting that natural products exhibit excellence in terms of safety and efficacy, presenting a wealth of biological activities and pharmacological effects [6,7]. Recently, scholars have demonstrated substantial interest in investigating natural compounds and their derivatives concerning the therapeutic management of PD [8,9]. Cordycepin (cordycepsin) is the main active ingredient (especially nucleosides) in Cordyceps militaris, possessing a variety of bioactivities and pharmacological effects [[10], [11], [12]], including antioxidant [13], anti-inflammatory [14], antiapoptotic [15], and antitumor effects [16]. Several studies have shown that cordycepin inhibits microglia activation [17], inhibits the TLR/NF-κB signaling pathway to attenuate oxidative stress and inflammatory responses [18,19], and also shows neuroprotective properties through anti-apoptotic mechanisms of the mitochondrial pathway [20]. Recent research indicates that cordycepin enhances cognitive function in mice afflicted with PD through the modulation of adenosine A2A receptors [21], providing new scientific evidence for the protective role of cordycepin in PD models. Some studies have highlighted the potential role of cordycepin in resisting neuroinflammation [14,22], rendering it a promising candidate for PD treatment; however, it remains necessary to conduct more in-depth studies to provide further insight into the mechanism of how cordycepin exerts its protective effects on PD models through complex signaling pathways.

Within mammals, the mitogen-activated protein kinase (MAPK) signaling pathway, encompassing extracellular regulated protein kinases (ERK), cJun N-terminal kinase (JNK), and p38 MAPK signaling cascades, assumes a pivotal role in diverse cellular processes, including cell growth, proliferation, autophagy, and apoptosis [23]. Previous studies have shown that proper regulation of the MAPK signaling pathway has positive significance for treating PD models [24,25]. Similarly, the PI3K/AKT signaling pathway plays an indispensable role in signal transduction and biological activities such as cell growth, death, self-digestion, metabolism, and transformation [26]. Numerous studies have demonstrated the significant involvement of the PI3K/AKT signaling pathway in models of PD [27,28]. Cordycepin mitigates inflammation and apoptosis induced by palmitate in vascular endothelial cells through the PI3K/AKT/eNOS signaling pathway [29]. Autophagy, a cellular process aimed at disassembling cells by eliminating damaged proteins and organelles, has significantly contributed to the understanding of the development of PD [30]. The mTOR signaling pathway stands out as a prominently characterized regulatory pathway in autophagy, influenced by various signaling pathways. Among these, the PI3K/AKT/mTOR pathway assumes a paramount role, contributing significantly to signal transduction and pivotal biological processes, including proliferation, apoptosis, metabolism, and angiogenesis [31,32]. The PI3K/AKT/mTOR pathway exhibits the capability to interact with various pathways, including MAPK, AMPK, JNK, and Ras [33,34]. Zearalenone triggers apoptosis and promotes cytoprotective autophagy in chicken granulosa cells through the PI3K/AKT/mTOR and MAPK signaling pathways [35]. Furthermore, within microglia, the inhibition of autophagy exacerbates dopaminergic neuron degeneration, resulting in heightened neuroinflammation in the striatum and substantia nigra [36,37]. Cordycepin slows the progression of PD by inhibiting the production of inflammatory factors in activated microglia [17]. Nevertheless, the neuroprotective effects of cordycepin in PD, especially the regulation of autophagy through signaling pathways such as PI3K/AKT/mTOR and MAPK, remain uncertain, and the involvement of microglial autophagy in this process remains unclear.

In the present study, we utilized an MPTP-induced experimental mouse model to thoroughly investigate the diverse molecular mechanisms underlying the neuroprotective effects of cordycepin in PD. Consequently, we explored the effects of cordycepin on motor and non motor dysfunction, protection of dopaminergic neurons, and inhibition of neuroinflammation. Additionally, proteomics and phosphoproteomics were employed to comprehensively investigate molecular interactions and regulatory networks in vivo. Finally, the BV2 cell model was constructed using MPP+, and the possibility of molecular mechanism was verified by in vitro and in vivo experiments. In summary, the objective of this study is to explore molecular-level mechanisms, offering novel insights into the pathogenesis of PD and presenting fresh molecular perspectives on the neuroprotective role of cordycepin in PD.