Key findings: (1) PD patients demonstrated significantly lower circulating irisin compared to controls (mean 2.1 ± 0.8 ng/mL versus 3.9 ± 1.2 ng/mL, p < 0.001), (2) irisin inversely correlated with disease severity (Spearman r = −0.58, p < 0.001), (3) physically active PD patients showed higher irisin than sedentary counterparts but remained below control levels, and (4) irisin weakly correlated with UPDRS motor score (r = −0.42) and cognitive function (MoCA score, r = 0.35). This evidence concerns the gene FNDC5 and Parkinson disease.