Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, affecting over 8.5 million individuals globally. Its pathophysiology is multifactorial, encompassing progressive loss of dopaminergic neurons in the substantia nigra, accumulation of misfolded alpha-synuclein, mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired proteostasis. Despite decades of research, current treatments remain predominantly symptomatic, with levodopa and dopamine replacement therapies failing to halt neurodegeneration. Given the high cost and low success rate of de novo drug development, both repurposed approved drugs and mechanistically targeted investigational therapeutics have emerged as promising approaches as a strategically rational alternative that leverages established safety profiles, known pharmacokinetics, and abbreviated regulatory pathways. This review aimed to comprehensively examine the current evidence for repurposed drugs, clinically investigated therapeutic candidates, and repositioning strategies targeting the principal pathological hallmarks of Parkinson's disease: (1) alpha-synuclein aggregation and propagation, (2) oxidative stress, (3) neuroinflammation, (4) mitochondrial dysfunction, (5) lysosomal and proteasomal dysfunction, and (6) dopaminergic neurodegeneration. The review further sought to identify recurring translational challenges, propose mechanistic frameworks for rational combination therapy, and outline future directions for trial design and biomarker integration. A narrative review of published preclinical studies, clinical trials, and recent literature was conducted, focusing on repurposed compounds with mechanistic plausibility and evidence of CNS penetration relevant to PD pathology. Evidence from Phase 1-3 clinical trials and post-mortem neuropathological analyses was synthesised across each pathological hallmark. Compounds were evaluated for mechanistic specificity, pharmacokinetic suitability, and clinical translation status. Across six pathological hallmarks, repurposed agents showed disease-relevant activity, with variable clinical translation. Ambroxol, a GCase pharmacological chaperone, achieved ~ 30-34% brain penetration, increased cerebrospinal fluid alpha-synuclein in a Phase 2 trial (n = 17) regardless of GBA mutation status, and is now in Phase 3 (ASPro-PD, n = 330). N-acetylcysteine restored depleted brain glutathione, scavenged reactive oxygen species, preserved VMAT2 and tyrosine hydroxylase expression, and improved motor outcomes, with positive dopamine transporter imaging in clinical studies. Doxycycline, a BBB-penetrant antibiotic, suppressed microglial MMP-3 and MMP-9 and downregulated TNF-α, IL-1β, iNOS, and COX-2 in preclinical PD models. Metformin and its mitochondria-targeted analog Mito-Met activated AMPK signalling and reversed mitochondrial dysfunction in PD models; however, Mito-Q10 failed in a one-year clinical trial, highlighting that ~ 70% of dopaminergic neurons are already lost at symptom onset, making intervention timing a decisive variable. For proteostatic dysfunction, the USP14 inhibitor IU1 enhanced both proteasomal and autophagic flux, though neurotoxicity above 200 µM limits its therapeutic window; BIIB122, a selective LRRK2 inhibitor, achieved CNS target engagement in Phase 1/2 trials, but its Phase 3 LIGHTHOUSE study was terminated, with Phase 2b LUMA ongoing. In dopaminergic neurodegeneration, GLP-1 receptor agonists produced divergent outcomes: Exenatide-PD3 (n = 231) showed no benefit over placebo, whereas LixiPark demonstrated reduced motor progression in early-stage PD, revealing that mechanistic equivalence does not guarantee clinical equivalence across heterogeneous patient populations. Drug repurposing represents a viable and strategically advantageous approach to targeting PD pathophysiology. Repurposed compounds, including ambroxol, N-acetylcysteine, doxycycline, metformin, and GLP-1 receptor agonists, demonstrate engagement with disease-relevant mechanisms and, in several cases, preliminary evidence of clinical activity. However, a recurring translational challenge is the timing of therapeutic intervention: with approximately 70% of dopaminergic neurons already lost at symptom onset, even mechanistically sound agents may fail if administered too late. Divergent GLP-1 trial outcomes underscore that mechanistic equivalence does not guarantee clinical equivalence, and that disease-stage heterogeneity is a critical confounder. Future priorities must include: (i) precision stratification by genetic profile (e.g., GBA and LRRK2 variants); (ii) combination therapies targeting multiple interconnected hallmarks simultaneously; (iii) development of validated fluid and neuroimaging biomarkers for early-stage patient selection; and (iv) adaptive trial designs that accommodate heterogeneity across the PD population. Integration of computational tools network pharmacology, machine learning, and systems biology with biomarker-defined clinical enrichment will be essential for accelerating repurposed candidates toward meaningful disease modification.
