PACAP in Parkinson's disease: A multifunctional neuropeptide at the crossroad of autophagy, inflammation, and metabolic repurposing.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the accumulation of α-synuclein, mitochondrial dysfunction, and chronic neuroinflammation. In this complex pathology, pituitary adenylate cyclase-activating polypeptide (PACAP) has become a crucial neuroprotective regulator; however, its signaling pathways are markedly impaired in Parkinson's disease (PD). This review consolidates the increasing evidence that PACAP counteracts the pathogenesis of PD through multiple mechanisms: restoring autophagic flux, diminishing oxidative stress, altering the balance from pro-apoptotic to anti-apoptotic pathways, and alleviating microglial-mediated neuroinflammation. Recognizing the difficulties associated with peptide-based therapies, we explore novel strategies to utilize PACAP's protective properties, including the repurposing of FDA-approved medications like linagliptin and metformin, which engage PACAP-dependent pathways. Despite preclinical models consistently demonstrating significant neuroprotective effects, there is a marked absence of clinical validation. This review integrates mechanistic insights, evidence from particular models, and potential biomarkers to establish PACAP as a promising therapeutic target and delineates a strategy for accelerating its transition from laboratory research to clinical application in PD.