Bilirubin as a Modulator of WNK1 Protein Signaling: Implications for Neuroinflammatory Diseases

Previously regarded merely as a potentially harmful waste product of heme catabolism, bilirubin has now emerged as a pleiotropic molecule with potent antioxidant, anti-inflammatory, and hormone-like properties. Recent findings have revealed protective effects against cardiovascular, metabolic, autoimmune, and neoplastic diseases, as well as neurological disorders. The growing understanding of neuroinflammatory processes has opened new avenues for exploring the role of bilirubin in neuroprotection. Despite the increasing number of studies investigating the protective effects of bilirubin in neurological diseases, the molecular mechanisms underlying its anti-inflammatory actions in the brain remain insufficiently understood. In this perspective article, With-No-Lysine (K) kinase 1 (WNK1) is discussed as a newly identified molecular target of bilirubin, highlighting its potential implications for neuroinflammatory diseases. The bilirubin-WNK1 axis may represent a previously unrecognized protective mechanism that could be leveraged to mitigate inflammation-driven neurodegeneration. This interaction can open new therapeutic opportunities for neurodegenerative disorders such as multiple sclerosis (MS), Alzheimer's disease, and Parkinson's disease.