Doxorubicin-induced hepatotoxicity: a multifaceted pathogenesis from mitochondrial collapse to immune remodeling and...

Doxorubicin's clinical utility is constrained by cumulative toxicities, including a significantly underestimated hepatotoxicity. As the primary metabolic hub, the liver accumulates doxorubicin via active transport, leading to mitochondrial crisis through quinone redox cycling and concurrent blockade of mitophagic flux. This drives hepatocytes toward synchronized regulated cell death, prominently featuring ferroptosis and pyroptosis. The injury is amplified by hepatic immune remodeling, characterized by Kupffer cell depletion and the formation of neutrophil extracellular traps. Furthermore, a proposed epigenetic component, driven by DNA hypomethylation and histone acetylation imbalances, may contribute to persistent hepatic dysfunction. By integrating these multidimensional mechanisms, this review evaluates forward-looking strategies, highlighting the potential of natural products, intelligent nanodelivery systems, and repurposed drugs to achieve hepatoprotection while critically addressing the inherent challenge of avoiding tumor protection.