Synergistic pathways in Parkinson's disease: The promise of FGF21 and ACE2.

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder globally, is pathologically characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN). Current therapeutic strategies primarily alleviate clinical symptoms but lack efficacy in halting or reversing neurodegeneration. Recent studies have highlighted the FGF21-ACE2 signaling axis-a synergistic interaction between fibroblast growth factor 21 (FGF21) and angiotensin-converting enzyme 2 (ACE2)-as an emerging therapeutic target in PD due to its tripartite roles in neuroprotection, anti-inflammatory modulation, and metabolic homeostasis. Mechanistically, FGF21 activates neuroprotective pathways including phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and the extracellular signal-regulated kinase (ERK)1/2, suppressing apoptotic cascades, amplifying antioxidant defenses, and stimulating dopaminergic neuron differentiation. Conversely, ACE2 counterbalances neurotoxicity by converting angiotensin II (Ang II) to angiotensin-(1-7) [Ang-(1-7)], thereby mitigating neuroinflammation and oxidative stress. Their coordinated activity potently inhibits M1 microglial activation, downregulates pro-inflammatory cytokines (e.g., TNF-α), and bolsters astrocytic antioxidant responses while preserving metabolic equilibrium. Notably, this axis ameliorates mitochondrial dysfunction and attenuates α-synuclein (α-syn) aggregationvia modulation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling networks, collectively decelerating PD pathogenesis. Therapeutic interventions such as small-molecule agonists (e.g., diminazene aceturate, DIZE) and CRISPR-Cas9-mediated gene editing show potential to upregulate FGF21-ACE2 activity, while non-pharmacological approaches including exercise and ketogenic diets may synergistically enhance pathway efficacy. However, translational hurdles persist, including limited blood-brain barrier (BBB) permeability of therapeutics, off-target effects, and insufficient clinical validation. Future directions should prioritize deciphering dynamic molecular crosstalk within this pathway, engineering BBB-penetrant nanocarriers for targeted delivery, and conducting large-scale randomized controlled trials. This review underscores the FGF21-ACE2 axis as a multi-mechanistic therapeutic paradigm for PD, with its capacity for simultaneous modulation of neurodegeneration, inflammation, and metabolism positioning it as a superior candidate to conventional single-target therapies in achieving disease modification.