Review argues that physiological or mildly elevated bilirubin can protect nigrostriatal dopaminergic neurons via antioxidant, anti-inflammatory and anti-ferroptotic actions and by modulating developmental pathways (Nrf2, microglial M2 polarization, Wnt/β-catenin, Shh).

Connects bilirubin to multiple PD-relevant, potentially druggable mechanisms (mitochondrial protection, Nrf2 activation, ferroptosis inhibition, immune modulation) that justify translational work on bilirubin-based therapies or mimetics despite current lack of direct interventional data.

INTRODUCTION: The progressive loss of dopaminergic neurons in the nigrostriatal pathway, driven by mechanisms such as oxidative stress, neuroinflammation, and ferroptosis, represents a hallmark of Parkinson's disease (PD). Notably, physiological or mildly elevated bilirubin levels demonstrate potent antioxidant and anti-inflammatory properties. This positions bilirubin as a compelling endogenous molecule with potential neuroprotective significance in PD. Furthermore, emerging evidence links early embryonic neurodevelopmental impairments to long-term PD risk, revealing a new dimension for protective interventions. METHODS: This review synthesizes current evidence on the protective roles of bilirubin against PD, detailing its mechanisms in countering oxidative stress, modulating neuroinflammation, inhibiting ferroptosis, and supporting normal development of nigrostriatal dopaminergic circuits. Key molecular pathways-including Nrf2 activation, microglial polarization, and developmental signaling pathways such as Wnt/β-catenin and Shh-are critically examined. RESULTS: Our analysis demonstrates that bilirubin directly neutralizes reactive species, preserves mitochondrial integrity, and promotes an anti-inflammatory milieu by inducing M2 microglia and modulating T-cell populations. Bilirubin also mitigates dopaminergic neuron injury by reducing iron deposition and activating the Nrf2 pathway. Beyond these classical mechanisms, bilirubin may fundamentally shape PD risk by orchestrating early embryonic development of dopaminergic neurons through key morphogenic signals, thereby ensuring robust neural circuit formation. DISCUSSION: This review explores the multifaceted potential of bilirubin, framing it not only as a neuroprotectant against established PD pathologies but also as a developmental modulator. By integrating insights from neural development and classical neurodegeneration, this work will inspire future translational research into bilirubin-based therapeutic strategies to prevent or modify the progression of PD.