Exploring the bioactivity of bilirubin and phyllobilins in atherosclerosis: functional insights and future mechanistic investigations

Atherosclerosis-driven cardiovascular diseases remain the leading cause of mortality worldwide. Epidemiological studies suggest that individuals with slightly elevated serum bilirubin levels may have a lower risk of developing atherosclerosis [ 1 ]. Structurally related phyllobilins, derived from chlorophyll breakdown in plants, are found in dietary and medicinal plants, and may also influence health [ 2 ]. This study explores the potential roles of bilirubin and phyllobilins in cellular mechanisms relevant to atherosclerosis. To assess their bioactivity, we conducted a series of in vitro assays modeling processes involved in atherosclerosis. Using primary human cells—including human umbilical vein endothelial cells, human aortic smooth muscle cells, and peripheral blood mononuclear cells—we investigated the effects of five phyllobilins and bilirubin in atherosclerosis-relevant in vitro assays. Results demonstrated that bilirubin and phyllobilins were unable to inhibit the key event in the pathogenesis of atherosclerosis, the adhesion of leukocytes to inflamed endothelial cells. However, they exhibited intriguing bioactivities against other relevant processes: (i) They exhibited antioxidant activity by reducing oxidative stress in vitro and in living cells, which may help prevent lipid oxidation. (ii) Bilirubin but not phyllobilins significantly decreased oxidized low-density lipoprotein uptake by macrophages, a crucial step in foam cell formation. (iii) One phyllobilin, Cj-PxB, significantly suppressed vascular smooth muscle cell proliferation and migration. Both processes are central to plaque development. While we describe several functional effects, the mechanism by which phyllobilins inhibit the functions of vascular smooth muscle cells and macrophages remain unknown. Further research is needed to determine potential therapeutic relevance in this context. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany