The article by Barañano et al. explores the physiologic role of bilirubin, a pigment that causes jaundice, as a potent antioxidant and cytoprotectant. Bilirubin, derived from the reduction of biliverdin by biliverdin reductase (BVR), is shown to protect cells from high concentrations of hydrogen peroxide (H2O2). The authors demonstrate that depletion of bilirubin through RNA interference significantly increases reactive oxygen species (ROS) levels and causes apoptotic cell death, highlighting the importance of bilirubin in cellular protection. They propose that the antioxidant actions of bilirubin are due to an amplification cycle where bilirubin is oxidized to biliverdin and then recycled back to bilirubin by BVR. This cycle provides a significant antioxidant effect, explaining the low concentrations of bilirubin required to exert its protective actions. The study also compares the antioxidant actions of bilirubin to those of glutathione (GSH), finding that both systems are crucial for protecting cells from oxidative stress. The findings suggest that the cytoprotective role of the BVR cycle may be the primary function of the mammalian bilirubin generating system. Additionally, the clinical relevance of these findings is discussed, noting that high plasma bilirubin levels are associated with reduced risk of coronary heart disease and other health benefits.The article by Barañano et al. explores the physiologic role of bilirubin, a pigment that causes jaundice, as a potent antioxidant and cytoprotectant. Bilirubin, derived from the reduction of biliverdin by biliverdin reductase (BVR), is shown to protect cells from high concentrations of hydrogen peroxide (H2O2). The authors demonstrate that depletion of bilirubin through RNA interference significantly increases reactive oxygen species (ROS) levels and causes apoptotic cell death, highlighting the importance of bilirubin in cellular protection. They propose that the antioxidant actions of bilirubin are due to an amplification cycle where bilirubin is oxidized to biliverdin and then recycled back to bilirubin by BVR. This cycle provides a significant antioxidant effect, explaining the low concentrations of bilirubin required to exert its protective actions. The study also compares the antioxidant actions of bilirubin to those of glutathione (GSH), finding that both systems are crucial for protecting cells from oxidative stress. The findings suggest that the cytoprotective role of the BVR cycle may be the primary function of the mammalian bilirubin generating system. Additionally, the clinical relevance of these findings is discussed, noting that high plasma bilirubin levels are associated with reduced risk of coronary heart disease and other health benefits.