Tannic acid protects against lapatinib-induced hepatotoxicity by inhibiting cathepsin activity and repairing lysosomal membrane permeabilization.

Lapatinib is an important targeted drug used to treat HER2-positive breast cancer. However, its hepatotoxicity restricts its clinical efficacy. This study aims to elucidate the molecular mechanism of lapatinib's hepatotoxicity. Through in vivo models, we found that lapatinib treatment led to significant increases in serum ALT/AST levels and pathological damage to liver tissue in mice. It also induced a decrease in mitochondrial membrane potential and cell apoptosis in AML12 liver cells in vitro. Furthermore, this study revealed that lapatinib causes damage to both the mitochondria and the lysosomes. This led to lysosomal membrane permeabilization (LMP) and blocked mitochondrial autophagy, resulting in cathepsin leakage into the cytoplasm. Based on these findings, we discovered that the FDA-approved food additive tannic acid (TA) as a cathepsin inhibitor can effectively protect liver cells and alleviate liver damage in mice without affecting lapatinib's ability to kill SKBR3 breast cancer cells. This study has revealed a new mechanism of lapatinib hepatotoxicity involving the lysosome for the first time, providing a new target and an experimental basis for developing selective liver protection strategies in clinical practice.