Deciphering the modulatory role of short-chain fatty acids in Parkinson’s disease via phosphorylation-dependent signaling mechanisms

Parkinson's disease (PD), the world's second most prevalent neurodegenerative disorder, is characterized by progressive neuronal degeneration mediated through intricate pathological mechanisms. Phosphorylation signaling pathways have been increasingly recognized as critical modulators in the development and progression of PD. Meanwhile, short-chain fatty acids (SCFAs), primarily produced by gut microbiota, have shown considerable neuroprotective potential by promoting autophagy, alleviating mitochondrial dysfunction, and regulating neuroinflammatory responses. Recent research suggests that SCFAs may influence the phosphorylation dynamics of key signaling pathways, including MAPKs, NF-κB, JAK/STAT, PI3K/Akt, AMPK, and Nrf2/Keap1/ARE, thereby modulating disease pathophysiology. This review aims to systematically evaluate how SCFAs modulate phosphorylation pathways to influence neuroinflammation, α-synuclein aggregation, and mitochondrial dysfunction in PD. By investigating this issue, we identify potential molecular targets and propose future research directions, offering new insighreviewts and strategies for the development of novel therapeutic and preventive interventions for PD.