Bilirubin and the Yellow Players in Ferroptosis: A Delicate Balance in Human Health and Disease, with a Focus on the Liver, Cardiovascular System, and Brain

Ferroptosis is a unique form of regulated lytic cell death driven by intracellular iron overload, excessive production of reactive oxygen species, failure of antioxidant defense systems, lipid peroxidation, and subsequent plasma membrane damage. Its initiation and progression involve complex signaling and regulatory networks. Although iron is a defining feature of ferroptosis, it also plays a central role in the heme oxygenase (HO)–biliverdin reductase (BVR) system, a cellular machinery associated with a lower prevalence of chronic diseases and reduced all-cause mortality. The HO–BVR cycle and its products biliverdin and bilirubin (together the yellow players: YPs) act as hormones and transcription factors on multiple signaling pathways, with powerful antioxidant, anti-inflammatory, and many more properties. The convergence between the two systems is suggestive of the existence of a finely tuned balance between the beneficial vs. exacerbating damage effects. Exploration of this equilibrium has just started. This review summarizes the current evidence on the interplay between ferroptosis and the HO–BVR system, in the context of liver, cardiovascular and brain diseases. We also review the therapeutic strategies aimed at modulating these pathways, considering both their potential benefits and their possible adverse consequences within the context of these integrated cellular defense and injury mechanisms.