# Inhibition of Cathepsin B protects against vandetanib-induced hepato-cardiotoxicity by restoring lysosomal damage

## TL;DR

A compound called tannic acid can protect against liver and heart damage caused by the cancer drug vandetanib without reducing its effectiveness.

## Contribution

The study identifies cathepsin B as a key mediator of toxicity and introduces tannic acid as a protective adjuvant for vandetanib.

## Key findings

- Cathepsin B (CTSB) mediates vandetanib-induced hepato-cardiotoxicity via lysosomal dysfunction and MCOLN1-calcium-AMPK disruption.
- Tannic acid inhibits CTSB and prevents toxicity without affecting vandetanib's antitumor activity in preclinical models.
- The findings suggest a shared lysosomal injury mechanism across organs, offering a strategy to prevent multi-organ toxicities in cancer therapies.

## Abstract

Vandetanib, a critical therapy for advanced thyroid and RET-driven cancers, is limited by life-threatening hepato-cardiotoxicity. This study identifies lysosomal protease cathepsin B (CTSB) as the central mediator of vandetanib-induced organ damage through STAT3-driven transcriptional activation. CTSB triggers mitochondrial apoptosis by cleaving the lysosomal calcium channel mucolipin TRP cation channel 1 (MCOLN1), disrupting calcium/AMP-activated protein kinase (AMPK) signaling and autophagy flux. Crucially, the natural compound tannic acid directly binds and inhibits CTSB, completely protecting against hepato-cardiotoxicity without compromising vandetanib's antitumor efficacy in preclinical models. Overall, our findings establish CTSB-mediated lysosomal dysfunction and MCOLN1-calcium-AMPK axis disruption as the core mechanism of vandetanib-induced hepato-cardiotoxicity, and identify tannic acid as a readily translatable adjuvant strategy to prevent this toxicity. These findings redefine CTSB as a druggable target for kinase inhibitor toxicities and position tannic acid as a clinically translatable adjuvant to enhance vandetanib's safety profile. By preserving lysosomal function and calcium homeostasis, this strategy addresses a critical unmet need in precision oncology, enabling prolonged, safer use of vandetanib and related tyrosine kinase inhibitors. The discovery of shared lysosomal injury mechanisms across organs also opens avenues for preventing multi-organ toxicities in broader cancer therapies.