Bidirectional Mechanisms Linking Circadian Rhythm Disruption and Parkinson's Disease: Chronobiomarkers and Therapeutic Implications.

Parkinson's disease (PD) is a progressive neurodegenerative disorder in which circadian rhythm disruption (CRD) emerges as both a prodromal feature and a potential pathogenic driver. Elucidating the bidirectional interplay between PD and CRD is essential for identifying early biomarkers and developing chronotherapeutic strategies. We narratively synthesized literature published over the past two decades in PubMed, Web of Science, and CNKI, focusing on molecular mechanisms, clinical manifestations, biomarker development, and interventional studies addressing the PD-CRD interface. In the CRD-PD direction, circadian disruption accelerates dopaminergic neurodegeneration through four convergent mechanisms: (i) REV-ERBα-mediated dysregulation of dopamine biosynthesis and NF-κB/NLRP3-driven neuroinflammation; (ii) impaired sleep-dependent glymphatic clearance of α-synuclein (α-syn); (iii) NAD+-SIRT1-BMAL1-PGC-1α axis dysfunction leading to mitochondrial bioenergetic failure; and (iv) C/EBPβ-dependent autophagic rhythm disruption coupled with pro-inflammatory microglial activation, collectively establishing a dual pro-inflammatory-autophagy-suppressive milieu permissive for α-syn aggregation. In the reverse PD-CRD direction, PD pathology destabilizes the circadian system via Braak-stage degeneration of rhythm-regulatory nuclei, retinal dopaminergic denervation attenuating SCN photic entrainment, pineal-melatonin axis suppression, iatrogenic effects of dopaminergic pharmacotherapy, and gut microbiota dysbiosis propagated through the microbiota-gut-brain axis. Emerging multi-modal chronobiomarkers-including peripheral clock gene expression profiles, melatonin secretion patterns, tryptophan-kynurenine metabolites, and gut microbial oscillation signatures-show promise for prodromal diagnosis and disease subtyping. Circadian-targeted precision interventions-encompassing timed bright light therapy, exogenous melatonin, and chronopharmacological interventions-represent a promising translational paradigm for the early identification and management of PD.