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PD is characterized by progressive degeneration of nigral dopaminergic neurons and is associated with elevated oxidative stress due to mitochondrial dysfunction. In this study, using a ratiometric bilirubin probe, we revealed that the mitochondrial inhibitor, rotenone, which is widely used to create a PD model, significantly decreased intracellular bilirubin levels in HepG2 cells. Chemical screening showed that BRUP\u20101 was a top hit that restored cellular bilirubin levels that were lowered by rotenone. We found that BRUP\u20101 up\u2010regulated the expression level of heme oxygenase\u20101 (HO\u20101), one of the rate\u2010limiting enzyme of bilirubin production via nuclear factor erythroid 2\u2010related factor 2 (Nrf2) activation. In addition, we demonstrated that this Nrf2 activation was due to a direct inhibition of the interaction between Nrf2 and Kelch\u2010like ECH\u2010associated protein 1 (Keap1) by BRUP\u20101. Both HO\u20101 up\u2010regulation and bilirubin restoration by BRUP\u20101 treatment were significantly abrogated by Nrf2 silencing. In neuronal PC12D cells, BRUP\u20101 also activated the Nrf2\u2010HO\u20101 axis and increased bilirubin production, resulted in the suppression of neurotoxin\u2010induced cell death, reactive oxygen species production, and protein aggregation, which are hallmarks of PD. Furthermore, BRUP\u20101 showed neuroprotective activity against rotenone\u2010treated neurons derived from induced pluripotent stem cells. These findings provide a new member of Keap1\u2010Nrf2 direct inhibitors and suggest that chemical modulation of heme metabolism using BRUP\u20101 may be beneficial for PD treatment.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14997-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14997","type":"journal-article","created":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T07:20:31Z","timestamp":1583306431000},"page":"81-97","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["BRUP\u20101, an intracellular bilirubin modulator, exerts neuroprotective activity in a cellular Parkinson\u2019s disease 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