. 2025 Aug 23;11:256. doi: 10.1038/s41531-025-01113-w

Table 1.

Molecular targets of exercise-induced neuroprotection in Parkinson’s disease: mechanisms of action, modulation profiles, and cross-target interactions

Molecular targets	Mechanism of action	Exercise-induced modulation	interactions
irisin	Irisin levels decline with aging, contributing to age-related pathologies. This exercise-induced myokine counteracts disease progression by enhancing energy metabolism, cellular homeostasis (via optimized autophagy and mitochondrial quality control), and reducing oxidative stress and inflammation⁹⁶. Irisin ameliorates Parkinson’s disease pathology by suppressing glial inflammation through reduced NLRP3 inflammasome activation and IL-1β secretion, thereby promoting neurogenesis and alleviating cognitive impairment¹³⁷. Irisin reduces obesity and insulin resistance¹¹³. Irisin protects the BBB by regulating the expression activity of matrix metalloproteinase-9^99,134.	Aerobic exercise enhanced FNDC5/irisin expression^42,137.	Human CSF showed a positive correlation between irisin and BDNF¹³⁸.
BDNF	BDNF is a key motility-inducing regulator of a variety of neuroplastic processes, including adult dentate gyrus neurogenesis¹³⁹.	Moderate-to-high-intensity walking sustainably regulates BDNF and promotes adaptive brain changes¹³⁹. High-intensity aerobic exercise increases BDNF levels in peripheral blood²⁹.	Irisin stimulates the release of BDNF in the brain¹⁰⁰.
IGF-1	IGF-1 synergizes with SIRT1, SIRT3, and VEGF to regulate the activity of RAS in the substantia nigra, which helps to inhibit oxidative stress and inflammation and protect dopaminergic neurons⁸⁴.	Resistance exercise and treadmill running increase IGF-1 secretion^42,84.	IGF-1 synergizes with BDNF, lactate, irisin, and several other proteins to mediate the effects of exercise on brain plasticity⁴². IGF-1 synergizes with SIRT3, SIRT1, and VEGF to regulate RAS activity⁸⁴.
SIRT1	SIRT1 regulates the apoptosis/autophagy pathway and maintains mitochondrial integrity^82,87, improves mitochondrial function⁸². Regulating the activity of RAS in the substantia nigra, which helps to inhibit oxidative stress and inflammation in elderly rats and protect dopaminergic neurons⁸⁴.	Treadmill running upregulated levels of SIRT1⁸².	SIRT1 synergizes with IGF-1, SIRT3, and VEGF to regulate RAS activity⁸⁴.
SIRT3	SIRT3 exerts anti-aging benefits by regulating energy metabolism and mitochondrial biogenesis, reducing the vulnerability of dopaminergic neurons^83,84.	Treadmill running upregulated SIRT3 levels⁸². Regular exercise can upregulate SIRT3 expression in mammals^83,84.	SIRT3 synergizes with IGF-1, SIRT1, and VEGF to regulate RAS activity⁸⁴.
VEGF	Aerobic and anaerobic exercise affect brain plasticity through changes in the expression of trophic factors such as VEGF⁴².	Treadmill running upregulates the level of VEGF⁸².	VEGF synergizes with BDNF, lactate, and several other proteins to mediate the effects of exercise on brain plasticity⁴². VEGF synergizes with IGF-1, SIRT1, and SIRT3 to regulate the activity of RAS⁸⁴.
GDNF	GDNF can contribute to neuroplasticity by decreasing caspase-3 activity and DNA fragmentation^140,141.	Exercise upregulates the expression of GDNF⁸⁴.	GDNF and BMP-7 act synergistically to mitigate post-stroke cerebral infarction and motor deficits by suppressing caspase-3-mediated apoptosis (reducing DNA fragmentation) and promoting neuroplasticity^140,141.
DJ-1	DJ-1 is involved in cellular stress response and antioxidant protection to maintain mitochondrial function⁷⁶.	Exercise upregulates DJ-1 through pathways of RAGE and TLR signaling^76,77.	Co-involved in the maintenance of mitochondrial function⁷⁵.
BMPs	BMPs play a key role in neuronal survival and synaptic plasticity¹¹. BMP-7 promotes neuroplasticity by decreasing caspase-3 activity and DNA fragmentation¹⁴¹. BMP6/BMP2 regulates dopaminergic synapse development in nigrastriatum and midbrain limbic neurons, which is essential for dopaminergic signaling and function⁵⁰.	Exercise stimulates the production of BMP³¹.	BMPs, along with other neurotrophic factors, maintain synaptic plasticity and neuronal survival¹¹.
VEGF	VEGF is involved in regulating the activity of RAS, inhibiting oxidative stress and inflammation, and protecting dopaminergic neurons⁸⁴.	Treadmill running upregulates the level of VEGF⁸².	VEGF synergizes with BDNF, lactate, VEGF, and several other proteins to mediate motor effects on brain plasticity⁴².VEGF synergizes with IGF-1, SIRT3, and VEGF to regulate RAS activity^42,84.
GDF5	GDF5, a member of the BMP family, signals through the canonical Smad pathway independent of Ret. In α-synuclein-based rat models of Parkinson’s disease, viral vector-mediated delivery of GDF5 to the substantia nigra confers neuroprotection by preserving dopaminergic neurons and ameliorating motor deficits¹²⁸.	Involved in the regulation of skeletal muscle plasticity¹⁴².	As a member of the BMP family, GDF5 works in conjunction with other neurotrophic factors to protect dopaminergic neurons¹²⁸.