A comparative study of idarubicin and doxorubicin in a chemically-induced in vivo mouse model for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a major therapeutic challenge with limited systemic treatment options and suboptimal response rates. Anthracyclines such as doxorubicin (DOX) and idarubicin (IDA) are frequently used in clinical settings, including transarterial chemoembolization (TACE), yet their efficacy and adverse effects in HCC remain poorly defined. In this long-term in vivo study, we performed a head-to-head comparison of DOX and IDA in a chemically induced mouse model of HCC, using repeated dosing (twice weekly for three weeks) to mimic clinical exposure similar to TACE. Both treatments induced significant weight loss and spleen enlargement, with IDA exhibiting a more pronounced systemic impact. While neither compound significantly altered tumor burden, both agents unexpectedly reduced hepatic collagen deposition and fibrosis. Mechanistically, DOX decreased hepatic stellate cell (HSC) activation without major changes in fibrotic markers, whereas IDA paradoxically increased HSC activation and upregulated TGF-β and CTGF expression. Both DOX and IDA activated endoplasmic reticulum (ER) stress pathways in non-tumorous liver tissue, particularly through the PERK axis. IDA treatment was associated with a strong upregulation of ATF4 in hepatocytes and enhanced macrophage recruitment, suggesting an impact on the hepatic microenvironment. Despite comparable tumor control, the divergent stromal and inflammatory responses may help explain differences in toxicity and long-term outcomes observed clinically. Our findings emphasize the need to consider microenvironmental and stress-related pathways when selecting and optimizing anthracycline regimens for TACE.