Bilirubin metabolism and its application in disease prevention: mechanisms and research advances

The role of bilirubin, a product of heme metabolism, has evolved from a traditionally perceived metabolic waste product to a critical molecule with diverse biological roles. This article comprehensively reviews the metabolic functions of bilirubin and advances in its application for disease prevention. Bilirubin is primarily derived from hemoglobin catabolism in senescent erythrocytes. It is subsequently metabolized and excreted by the liver through tightly regulated processes involving enzymes, nuclear receptors, hormones, and pharmaceuticals. Bilirubin exhibits diverse physiological functions, including antioxidant, anti-inflammatory, and immunomodulatory activities. Owing to its unique chemical structure, bilirubin scavenges free radicals, inhibits lipid peroxidation, and protects cells across multiple systems. By suppressing the NF-κB signaling pathway, it reduces inflammatory factor release and mitigates chronic inflammation. Additionally, it modulates immune cell activity to maintain homeostasis, offering therapeutic potential for autoimmune and infectious diseases. Bilirubin demonstrates significant potential in disease prevention. In cardiovascular diseases, it attenuates atherosclerosis and mitigates myocardial ischemia/reperfusion injury. For metabolic disorders, it improves insulin resistance, regulates blood glucose, and reduces hepatic steatosis, offering therapeutic benefits for diabetes and non-alcoholic fatty liver disease. In neurological conditions, its antioxidant and anti-inflammatory properties hold promise for preventing and managing neurodegenerative diseases and neonatal bilirubin encephalopathy. Although research on bilirubin has advanced significantly, its intracellular targets and molecular interaction networks remain incompletely understood, and numerous challenges hinder its clinical translation. Future efforts should leverage multi-omics technologies to elucidate its mechanisms, develop intelligent and personalized therapeutics, and conduct large-scale clinical trials to accelerate translational applications and improve patient outcomes.