Irisin inhibits dopaminergic neuron lactate metabolism and repairs mitochondrial function to alleviate Parkinson’s disease by activating SIRT1 signaling pathway

Irisin, an exercise-induced myokine with promising therapeutic potential, exhibits neuroprotective effects in Parkinson's disease (PD). However, its underlying mechanisms remain poorly understood. This study investigated the role of irisin in an MPTP-induced mouse model of PD. Irisin treatment improved motor function, as evidenced by enhanced performance on the rotarod test, and promoted dopaminergic neuron survival, demonstrated by increased TH-positive cell counts and reduced α-synuclein accumulation. Additionally, irisin inhibited lactate metabolism in the substantia nigra by decreasing lactate and pyruvate levels and downregulating key glycolytic enzymes. Mitochondrial function was restored through reductions in oxidative stress markers and improvements in ATP synthesis and mitochondrial morphology. Furthermore, irisin activated the SIRT1 signaling pathway, leading to the deacetylation of HIF-1α and PGC-1α, which suppressed apoptosis and enhanced cell viability in MPP + -treated SH-SY5Y cells. Irisin also attenuated neuroinflammation by reducing microglial activation and protecting neurons from microglia-induced apoptosis. These findings demonstrate that irisin confers neuroprotection in PD through multiple mechanisms, including the regulation of motor function, dopaminergic neuron survival, mitochondrial function, and neuroinflammation. Activation of the SIRT1 pathway appears to be a core therapeutic target for these effects of irisin.