Plasma Proteomic Profiling of Proteostatic and Redox Pathway Alterations Following a Multimodal Hormetic Intervention in Parkinson’s Disease

Parkinson’s disease (PD) is associated with systemic proteostatic failure, chronic neuroinflammation, and mitochondrial abnormalities linked to severe oxidative stress. This exploratory longitudinal study mapped the deep-coverage plasma proteome (~6000 proteins via SOMAmer technology) in 32 patients with mild-to-moderate PD following a 21-day intensive, multimodal physiological stimulus framework. This hormetic intervention combined balneo- and hydropinic therapy (incorporating mineral water with 7.48 mg/L H2S and peloid mud with 6.14% S2− of dry matter), neurophysiotherapy, a neuroprotective MIND diet, mindfulness meditation, and clinical aromatherapy. Systems-level pathway analysis was leveraged to evaluate alterations in functional biological networks. Gene Set Enrichment Analysis (GSEA) resolved a negative enrichment of the Parkinson’s disease pathway hsa05012 (FDR = 0.0053). Network topology modeling revealed a highly coordinated proteostatic and antioxidant alteration pattern involving interferon-gamma (IFN-γ) and polyubiquitin-B (UBB) protein clusters (p = 2.2 × 10−5), accompanied by the downregulation of protein clearance markers (UBB, p62, and UCHL1). Concurrently, upregulation of the phase-II detoxification modifier sulfotransferase 1C2 (SULT1C2; log2FC = 0.42) and a reduction of circulating mitochondrial respiratory subunits (NDUFB6, COX5A, NDUFB11) were observed. These exploratory findings may suggest that multimodal hormetic interventions trigger systemic, redox-responsive changes in protein signatures. However, because the distinct volatile chemical and organoleptic properties of the intervention prevent a sham control, these open-label findings must be treated as hypothesis-generating. These tentative models require verification in future parallel-controlled trials before definitive causal interpretations can be established.