Metabolism-driven hepatotoxicity of 5-fluorouracil: molecular mechanisms and future therapeutic directions

5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent for the treatment of various solid malignancies; however, its clinical application is also associated with hepatotoxicity. As the liver is the primary site of 5-FU metabolism, excessive accumulation of the drug and its metabolites can lead to hepatic injury through multiple interconnected mechanisms. This review summarizes the current understanding of the 5-FU metabolism and molecular pathways involved in 5-FU-induced liver damage. Evidence indicates that 5-FU induces oxidative stress,which is a key event in its hepatotoxicity, characterized by excessive generation of ROS, depletion of antioxidant defenses, and oxidative damage to cellular macromolecules. Increased oxidative stress promotes lipid peroxidation, DNA damage, and mitochondrial dysfunction, ultimately leading to hepatocyte death. 5-FU-induced apoptosis is mediated by the activation of p53 signaling, disruption of the Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) balance, subsequent cytochrome c release, caspase activation, and DNA fragmentation. 5-FU induces Inflammatory responses by activation of nuclear factor kappa B signaling and transcription of pro-inflammatory cytokines, further aggravating hepatic injury. Emerging studies also suggest that necroptosis and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome contribute to the progression of 5-FU-induced liver injury. Additionally, impairment of mitochondrial fatty acid β-oxidation contributes to lipid accumulation and hepatic steatosis. Despite significant advances in understanding the pathogenesis of 5-FU-induced hepatotoxicity, several molecular pathways remain insufficiently explored. A comprehensive understanding of these mechanisms may facilitate the development of effective hepatoprotective interventions and improve the safety of 5-FU-based chemotherapy.